Therapeutically active compositions and their methods of use

ABSTRACT

Provided are compounds with the following structure, formula (I) pharmaceutically acceptable salts thereof, use of those compounds for treating cancer and pharmaceutical compositions comprising those compounds.

CLAIM OF PRIORITY

This application claims priority from Chinese Patent Application No. CN201110172169.1, filed Jun. 17, 2011, U.S. Ser. No. 61/509,071, filedJul. 18, 2011 and U.S. Ser. No. 61/584,210, filed Jan. 6, 2012, each ofwhich is incorporated by reference in its entirety.

BACKGROUND OF INVENTION

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylationof isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymesbelong to two distinct subclasses, one of which utilizes NAD(+) as theelectron acceptor and the other NADP(+). Five isocitrate dehydrogenaseshave been reported: three NAD(+)-dependent isocitrate dehydrogenases,which localize to the mitochondrial matrix, and two NADP(+)-dependentisocitrate dehydrogenases, one of which is mitochondrial and the otherpredominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known asIDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is theNADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm andperoxisomes. It contains the PTS-1 peroxisomal targeting signalsequence. The presence of this enzyme in peroxisomes suggests roles inthe regeneration of NADPH for intraperoxisomal reductions, such as theconversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as inperoxisomal reactions that consume 2-oxoglutarate, namely thealpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves asignificant role in cytoplasmic NADPH production.

The human IDH1 gene encodes a protein of 414 amino acids. The nucleotideand amino acid sequences for human IDH1 can be found as GenBank entriesNM_(—)005896.2 and NP_(—)005887.2 respectively. The nucleotide and aminoacid sequences for IDH1 are also described in, e.g., Nekrutenko et al.,Mol. Biol. Evol. 15:1674-1684 (1998); Geisbrecht et al., J. Biol. Chem.274:30527-30533 (1999); Wiemann et al., Genome Res. 11:422-435 (2001);The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al.,Submitted (December 2008) to UniProtKB; Kullmann et al., Submitted (June1996) to the EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science314:268-274 (2006).

Non-mutant, e.g., wild type, IDH1 catalyzes the oxidativedecarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD⁺(NADP⁺) to NADP (NADPH), e.g., in the forward reaction:

Isocitrate+NAD⁺(NADP⁺)→α-KG+CO₂+NADH (NADPH)+H⁺.

It has been discovered that mutations of IDH1 present in certain cancercells result in a new ability of the enzyme to catalyze theNAPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate(2HG). 2HG is not formed by wild-type IDH1. The production of 2HG isbelieved to contribute to the formation and progression of cancer (Dang,L et al, Nature 2009, 462:739-44).

The inhibition of mutant IDH1 and its neoactivity is therefore apotential therapeutic treatment for cancer. Accordingly, there is anongoing need for inhibitors of IDH1 mutants having alpha hydroxylneoactivity.

SUMMARY OF INVENTION

Described herein are compounds of Structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Y is —N(R⁵)—, —N(R₅)—CH₂—, —CH₂—N(R⁵)—, or —CH(R⁵)—;

each R^(1a) and R^(1b) is independently hydrogen, —C₁-C₄ alkyl,—N(R⁷)(C₁-C₄ alkylene)-N(R⁷)(C₁-C₄ alkyl), aryl, heteroaryl,heterocyclyl, —C(O)N(R⁷)-aryl, —N(R⁷)C(O)-aryl, —(C₁-C₄ alkylene)-aryl,—(C₁-C₄ alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-aryl, —O—(C₀-C₄alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-heterocyclyl, —O—(C₀-C₄alkylene)-carbocyclyl, —N(R⁷)-aryl, —N(R⁷)-heteroaryl, —N(R⁹)-aryl,—N(R⁹)-heteroaryl, —O—(C₁-C₄ alkeylene)-N(R⁷)C(O)O—(C₁-C₄alkylene)-aryl, or —N(R⁹)—C(O)—(C₂-C₄ alkenyl) wherein:

at least one of R^(1a) and R^(1b) is not hydrogen or methyl; anyalkylene moiety present in R^(1a) or R¹ is optionally substituted withOH or F;

each R⁷ is independently selected from hydrogen and C₁-C₄ alkyl; and

any aryl, carbocyclyl, heteroaryl, or heterocyclyl of R^(1a) or R^(1b)is optionally substituted with one or more substituents selected from-G-L-M, halo, —NO₂, C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃;

G is a bond or a bivalent C₁-C₆ saturated or unsaturated, straight orbranched hydrocarbon chain wherein optionally one, two or threemethylene units of the hydrocarbon chain are independently replaced by—NR⁸—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—,—C(═NR⁸)—, —N═N—, or —C(═N₂)—;

L is a covalent bond or a bivalent C₁₋₈ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one, two, or threemethylene units of L are optionally and independently replaced bycyclopropylene, —NR⁸—, —N(R⁸)C(O)—, —C(O)N(R⁸)—, —N(R⁸)SO₂—, SO₂N(R⁸)—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR⁸)—,—N═N—, or —C(═N₂)—;

M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partiallyunsaturated, or aromatic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, and wherein said ring issubstituted with at 1-4 groups independently selected from -D-E, oxo,NO₂, halogen, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

D is a covalent bond or a bivalent C₁-C₆ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one or two methyleneunits of D are optionally and independently replaced by —NR⁸—, —S—, —O—,—C(O)—, —SO—, or —SO₂—;

E is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinsaid alkyl, alkenyl or alkynyl is optionally substituted with oxo,halogen, or CN; and

each R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, —S(O)₂—C₂-C₄ alkenyl, —C₁-C₆ alkoxy, or an optionallysubstituted group selected from phenyl, a 4-7 membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R² is selected from phenyl, a 3-7 membered cycloalkyl, C₂-C₄ alkyl, orCF₃, wherein the phenyl or cycloalkyl is optionally substituted with asubstituent selected from methyl or fluoro;

each R³ is independently selected from halo, —(C₁-C₄ alkylene)-O—(C₁-C₄alkyl), —C₁-C₄ fluoroalkyl, —C(O)—O—(C₁-C₄ alkyl), -phenyl, -heteroaryl,C₃-C₇ cycloalkyl, —CH₂—N(C₁-C₄ alkyl)₂, C(O)—N—(C₁-C₄ alkyl)₂,—C(O)—NH—(C₁-C₄ alkyl), —C₁-C₄ alkyl optionally substituted with one ormore halo or —OH, or two R³s are taken together to form a 3-8 saturatedring or a fused phenyl wherein said saturated ring or fused phenyl isoptionally substituted with 1 to 2 methyl;

R⁴ is selected from hydrogen, —CN, halo, C₁-C₄ alkoxy, —CH₂NH(C₁-C₄alkyl), C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl),C₁-C₄ fluoroalkyl, C(O)—N—(C₁-C₄ alkyl)₂, —C(O)—NH—(C₁-C₄ alkyl),—C(O)—O—(C₁-C₄ alkyl), —C(O)—OH, —S(O)₂—(C₁-C₄ alkyl), and a 5-memberedheteroaryl;

R⁵ is selected from: —C(O)—(C₁-C₅ alkyl), —C(O)—(C₂-C₆ alkenyl),—C(O)—(C₀-C₂ alkylene)-Q, —C(O)—(C₁-C₄ alkenylene)-Q, —C(O)—(C₀-C₂alkylene)-N(R⁶)—(C₀-C₂ alkylene)-Q, —C(O)—O—(C₀-C₂ alkylene)-Q,—C(O)—(C₁-C₂ alkylene)-O—(C₀-C₂ alkylene)-Q, —C(O)—C(O)-Q, —S(O)₂-Q,—C(O)—(C₁-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl), —C(O)—N(R⁶)—(C₁-C₄alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—N(R⁶)—(C₁-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₁-C₆alkyl), —C(O)—(C₀-C₂ alkylene)N(R⁶)—(C₂-C₆ alkynyl), —C(O)—(C₀-C₂alkylene)-N(R⁶)—(C₂-C₆ alkenyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₀-C₂alkylene)-O—(C₁-C₄ alkyl), —C(O)—(C₁-C₂ alkylene)-O—(C₁-C₄ alkyl),—C(O)—(C₁-C₂ alkylene)-C(O)C(O)N(R)(C₁-C₄ alkyl), —C(O)—O—(C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —(C₀-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl),—(C₀-C₄ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₄ alkylene)-O—(C₁-C₄alkyl), —C(O)—(C₁-C₂ alkylene)-S(O)₀₋₂-(C₁-C₄ alkyl), —S(O)₂—(C₁-C₄alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)C(O)N(R⁶)(C₁-C₆ alkyl), —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂—(C₁-C₆ alkyl), or —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂Q, wherein:

-   -   any alkylene moiety present in R⁵ is optionally substituted with        OCH₃, OH or F;    -   any terminal methyl moiety present in R⁵ is optionally replaced        with —CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, C(O)CF₃, CN, —OCH₃,        —C(O)H, —OP(O)(OH)₂, —OP(O)(C₁-C₄ alkoxy)₂ or CO₂H;

each R⁶ is independently selected from hydrogen and methyl;

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl,wherein Q is optionally substituted with up to 3 substituentsindependently selected from C₁-C₄ alkyl optionally substituted with —OH,C₁-C₄ alkoxy, —C(O)O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy),—CN, —OH, fluoro, chloro, and bromo;

R⁹ is selected from aryl and heteroaryl, wherein each aryl or heteroarylis optionally substituted with one or more substituents selected from-G-L-M, halo, C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃; and

m is 0, 1, 2 or 3.

The compound of formula I inhibits mutant IDH1, particularly mutant IDH1having alpha hydroxyl neoactivity. Also described herein arepharmaceutical compositions comprising a compound of formula I or a saltthereof and methods of using such compositions to treat cancerscharacterized by the presence of a mutant IDH1.

DETAILED DESCRIPTION OF THE INVENTION

This invention is not limited in its application to the details ofconstruction and the arrangement of components set forth in thefollowing description or illustrated in the drawings. The invention iscapable of other embodiments and of being practiced or of being carriedout in various ways. Also, the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing”, “involving”, and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

DEFINITIONS

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁-C₁₂ alkyl indicates that the group may have from1 to 12 (inclusive) carbon atoms in it. The term “haloalkyl” refers toan alkyl in which one or more hydrogen atoms are replaced by halo, andincludes alkyl moieties in which all hydrogens have been replaced byhalo (e.g., perfluoroalkyl). The terms “arylalkyl” or “aralkyl” refer toan alkyl moiety in which an alkyl hydrogen atom is replaced by an arylgroup. Aralkyl includes groups in which more than one hydrogen atom hasbeen replaced by an aryl group. Examples of “arylalkyl” or “aralkyl”include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl,and trityl groups.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and —CH₂CH(CH₃)CH₂—.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and having one or more double bonds.Examples of alkenyl groups include, but are not limited to, allyl,propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doublebond carbons may optionally be the point of attachment of the alkenylsubstituent.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and characterized in having one or moretriple bonds. Examples of alkynyl groups include, but are not limitedto, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbonsmay optionally be the point of attachment of the alkynyl substituent.

The term “alkoxy” refers to an —O-alkyl radical. The term “haloalkoxy”refers to an alkoxy in which one or more hydrogen atoms are replaced byhalo, and includes alkoxy moieties in which all hydrogens have beenreplaced by halo (e.g., perfluoroalkoxy).

The term “aryl” refers to a fully aromatic monocyclic, bicyclic, ortricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl,naphthyl, and anthracenyl. Unless otherwise specified, any ring atom inan aryl can be substituted by one or more substituents.

The term “carbocyclyl” refers to a non-aromatic, monocyclic, bicyclic,or tricyclic hydrocarbon ring system. Carbocyclyl groups include fullysaturated ring systems (e.g., cycloalkyls), and partially saturated ringsystems.

The term “cycloalkyl” as employed herein includes saturated cyclic,bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12carbons. Any ring atom can be substituted (e.g., by one or moresubstituents). Examples of cycloalkyl moieties include, but are notlimited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, andnorbornyl.

The term “heteroaryl” refers to a fully aromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (or the oxidized forms such as N⁺—O⁻, S(O) and S(O)₂).

The term “heterocyclyl” refers to a nonaromatic, 3-10 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (or the oxidized forms such as N⁺—O⁻, S(O) and S(O)₂).The heteroatom may optionally be the point of attachment of theheterocyclyl substituent. Examples of heterocyclyl include, but are notlimited to, tetrahydropyranyl, tetrahydropyranyl, piperidinyl,morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclylgroups include fully saturated ring systems, and partially saturatedring systems.

Bicyclic and tricyclic ring systems containing one or more heteroatomsand both aromatic and non-aromatic rings where the point of attachmentfrom the ring system to the rest of the molecule is through anon-aromatic ring are considered to be heterocyclyl groups. Bicyclic ortricyclic ring systems where an aryl or a heteroaryl is fused to acarbocyclyl or heterocyclyl and the point of attachment from the ringsystem to the rest of the molecule is through an aromatic ring areconsidered to be aryl or heteroaryl groups.

Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclylgroups, either alone or a part of a group (e.g., the aryl portion of anaralkyl group), are optionally substituted at one or more substitutableatoms with, unless specified otherwise, substituents independentlyselected from: halo, —CN, C₁-C₄ alkyl, ═O, —OR^(b), —OR^(b′), —SR^(b),—SR^(b′), —(C₁-C₄ alkyl)-N(R^(b))(R^(b)), —(C₁-C₄alkyl)-N(R^(b))(R^(b′)), —N(R^(b))(R^(b)), —N(R)(R^(b′)), —O—(C₁-C₄alkyl)-N(R^(b))(R^(b)), —O—(C₁-C₄ alkyl)-N(R^(b))(R^(b′)), —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl)-N(R^(b))(R^(b)), —(C₁-C₄ alkyl)-O—(C₁-C₄alkyl)-N(R^(b))(R^(b′)), —C(O)—N(R^(b))(R^(b)), —(C₁-C₄alkyl)-C(O)—N(R^(b))(R^(b)), —(C₁-C₄ alkyl)-C(O)—N(R^(b))(R^(b′)),—OR^(b′), R^(b′), —C(O)(C₁-C₄ alkyl), —C(O)R^(b′),—C(O)N(R^(b′))(R^(b)), —N(R^(b))C(O)(R^(b)), —N(R^(b))C(O)(R^(b′)),—N(R^(b))SO₂(R^(b)), —SO₂N(R^(b))(R^(b)), —N(R^(b))SO₂(R^(b′)), and—SO₂N(R^(b))(R^(b′)), wherein any alkyl substituent is optionallyfurther substituted with one or more of —OH, —O—(C₁-C₄ alkyl), halo,—NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂;

each R^(b) is independently selected from hydrogen, and —C₁-C₄ alkyl; or

two R^(b)s are taken together with the nitrogen atom to which they arebound to form a 4- to 8-membered heterocyclyl optionally comprising oneadditional heteroatom selected from N, S, and O; and

each R^(b′) is independently selected from C₃-C₇ carbocylyl, phenyl,heteroaryl, and heterocyclyl, wherein one or more substitutablepositions on said phenyl, cycloalkyl, heteroaryl or heterocyclesubstituent is optionally further substituted with one or more of—(C₁-C₄ alkyl), —(C₁-C₄ fluoroalkyl), —OH, —O—(C₁-C₄ alkyl), —O—(C₁-C₄fluoroalkyl), halo, —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂.

Heterocyclyl groups, either alone or as part of a group, are optionallysubstituted on one or more any substitutable nitrogen atom with oxo,—C₁-C₄ alkyl, or fluoro-substituted C₁-C₄ alkyl.

The term “substituted” refers to the replacement of a hydrogen atom byanother group.

As used herein, the term “elevated levels of 2HG” means 10%, 20% 30%,50%, 75%, 100%, 200%, 500% or more 2HG then is present in a subject thatdoes not carry a mutant IDH1 allele. The term “elevated levels of 2HG”may refer to the amount of 2HG within a cell, within a tumor, within anorgan comprising a tumor, or within a bodily fluid.

The term “bodily fluid” includes one or more of amniotic fluidsurrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum,Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate,interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage orphlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears,urine, vaginal secretion, or vomit.

As used herein, the terms “inhibit” or “prevent” include both completeand partial inhibition and prevention. An inhibitor may completely orpartially inhibit the intended target.

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease/disorder (e.g.,a cancer), lessen the severity of the disease/disorder (e.g., a cancer)or improve the symptoms associated with the disease/disorder (e.g., acancer).

As used herein, an amount of a compound effective to treat a disorder,or a “therapeutically effective amount” refers to an amount of thecompound which is effective, upon single or multiple dose administrationto a subject, in treating a cell, or in curing, alleviating, relievingor improving a subject with a disorder beyond that expected in theabsence of such treatment.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patient(referred to as a patient) having a disorder, e.g., a disorder describedherein or a normal subject. The term “non-human animals” of theinvention includes all vertebrates, e.g., non-mammals (such as chickens,amphibians, reptiles) and mammals, such as non-human primates,domesticated and/or agriculturally useful animals, e.g., sheep, dog,cat, cow, pig, etc.

Compounds

Provided is a compound of Structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Y is —N(R⁵)—, —N(R₅)—CH₂—, —CH₂—N(R⁵)—, or —CH(R⁵)—;

each R^(1a) and R^(1b) is independently hydrogen, —C₁-C₄ alkyl,—N(R⁷)(C₁-C₄ alkylene)-N(R⁷)(C₁-C₄ alkyl), aryl, heteroaryl,heterocyclyl, —C(O)N(R⁷)-aryl, —N(R⁷)C(O)-aryl, —(C₁-C₄ alkylene)-aryl,—(C₁-C₄ alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-aryl, —O—(C₀-C₄alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-heterocyclyl, —O—(C₀-C₄alkylene)-carbocyclyl, —N(R⁷)-aryl, —N(R⁷)-heteroaryl, —N(R⁹)-aryl,—N(R⁹)-heteroaryl, —O—(C₁-C₄ alkeylene)-N(R⁷)C(O)O—(C₁-C₄alkylene)-aryl, or —N(R⁹)—C(O)—(C₂-C₄ alkenyl) wherein:

at least one of R^(1a) and R^(1b) is not hydrogen or methyl;

any alkylene moiety present in R^(1a) or R^(1b) is optionallysubstituted with OH or F;

each R⁷ is independently selected from hydrogen and C₁-C₄ alkyl; and

any aryl, carbocyclyl, heteroaryl, or heterocyclyl of R^(1a) or R^(1b)is optionally substituted with one or more substituents selected from-G-L-M, halo, —NO₂, C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃;

G is a bond or a bivalent C₁-C₆ saturated or unsaturated, straight orbranched hydrocarbon chain wherein optionally one, two or threemethylene units of the hydrocarbon chain are independently replaced by—NR⁸—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—,—C(═NR⁸)—, —N═N—, or —C(═N₂)—;

L is a covalent bond or a bivalent C₁₋₈ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one, two, or threemethylene units of L are optionally and independently replaced bycyclopropylene, —NR⁸—, —N(R⁸)C(O)—, —C(O)N(R⁸)—, —N(R⁸)SO₂—, SO₂N(R⁸)—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR⁸)—,—N═N—, or —C(═N₂)—;

M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partiallyunsaturated, or aromatic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, and wherein said ring issubstituted with at 1-4 groups independently selected from -D-E, oxo,NO₂, halogen, CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

D is a covalent bond or a bivalent C₁-C₆ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one or two methyleneunits of D are optionally and independently replaced by —NR⁸—, —S—, —O—,—C(O)—, —SO—, or —SO₂—;

E is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinsaid alkyl, alkenyl or alkynyl is optionally substituted with oxo,halogen, or CN; and

each R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, —C₁-C₆ alkoxy, —S(O)₂—C₂-C₄ alkenyl, or an optionallysubstituted group selected from phenyl, a 4-7 membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R² is selected from phenyl, a 3-7 membered cycloalkyl, C₂-C₄ alkyl, orCF₃, wherein the phenyl or cycloalkyl is optionally substituted with asubstituent selected from methyl or fluoro;

each R³ is independently selected from halo, —(C₁-C₄ alkylene)-O—(C₁-C₄alkyl), —C₁-C₄ fluoroalkyl, —C(O)—O—(C₁-C₄ alkyl), -phenyl, -heteroaryl,C₃-C₇ cycloalkyl, —CH₂—N(C₁-C₄ alkyl)₂, C(O)—N—(C₁-C₄ alkyl)₂,—C(O)—NH—(C₁-C₄ alkyl), —C₁-C₄ alkyl optionally substituted with one ormore halo or —OH, or two R⁵ are taken together to form a 3-8 saturatedring or a fused phenyl wherein said saturated ring or fused phenyl isoptionally substituted with 1 to 2 methyl;

R⁴ is selected from hydrogen, —CN, halo, C₁-C₄ alkoxy, —CH₂NH(C₁-C₄alkyl), C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl),C₁-C₄ fluoroalkyl, C(O)—N—(C₁-C₄ alkyl)₂, —C(O)—NH—(C₁-C₄ alkyl),—C(O)—O—(C₁-C₄ alkyl), —C(O)—OH, —S(O)₂—(C₁-C₄ alkyl), and a 5-memberedheteroaryl;

R⁵ is selected from: —C(O)—(C₁-C₅ alkyl), —C(O)—(C₂-C₆ alkenyl),—C(O)—(C₀-C₂ alkylene)-Q, —C(O)—(C₁-C₄ alkenylene)-Q, —C(O)—(C₀-C₂alkylene)-N(R⁶)—(C₀-C₂ alkylene)-Q, —C(O)—O—(C₀-C₂ alkylene)-Q,—C(O)—(C₁-C₂ alkylene)-O—(C₀-C₂ alkylene)-Q, —C(O)—C(O)-Q, —S(O)₂-Q,—C(O)—(C₁-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl), —C(O)—N(R⁶)—(C₁-C₄alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—N(R⁶)—(C₁-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₁-C₆alkyl), —C(O)—(C₀-C₂ alkylene)N(R⁶)—(C₂-C₀ alkynyl), —C(O)—(C₀-C₂alkylene)-N(R⁶)—(C₂-C₆ alkenyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₀-C₂alkylene)-O—(C₁-C₄ alkyl), —C(O)—(C₁-C₂ alkylene)-O—(C₁-C₄ alkyl),—C(O)—(C₁-C₂ alkylene)-C(O)C(O)N(R)(C₁-C₄ alkyl), —C(O)—O—(C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —(C₀-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl),—(C₀-C₄ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₄ alkylene)-O—(C₁-C₄alkyl), —C(O)—(C₁-C₂ alkylene)-S(O)₀₋₂-(C₁-C₄ alkyl), —S(O)₂—(C₁-C₄alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)C(O)N(R⁶)(C₁-C₆ alkyl), —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂—(C₁-C₆ alkyl), or —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂Q, wherein:

-   -   any alkylene moiety present in R⁵ is optionally substituted with        OCH₃, OH or F;    -   any terminal methyl moiety present in R⁵ is optionally replaced        with —CH₂OH,    -   CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, C(O)CF₃, CN, —OCH₃, —C(O)H,        —OP(O)(O)₂, —OP(O)(C₁-C₄ alkoxy)₂ or CO₂H;

each R⁶ is independently selected from hydrogen and methyl;

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl,wherein Q is optionally substituted with up to 3 substituentsindependently selected from C₁-C₄ alkyl optionally substituted with —OH,C₁-C₄ alkoxy, —C(O)O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy),—CN, —OH, fluoro, chloro, and bromo;

R⁹ is selected from aryl, and heteroaryl, wherein each aryl orheteroaryl is optionally substituted with one or more substituentsselected from -G-L-M, halo, C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃; and

m is 0, 1, 2 or 3.

In some embodiments, provided is a compound of Structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Y is —N(R⁵)— or —CH(R⁵)—;

each R^(1a) and R^(1b) is independently hydrogen, —C₁-C₄ alkyl,—N(R⁷)(C₁-C₄ alkylene)-N(R⁷)(C₁-C₄ alkyl), aryl, heteroaryl,heterocyclyl, —C(O)N(R⁷)-aryl, —N(R⁷)C(O)-aryl, —(C₁-C₄ alkylene)-aryl,—(C₁-C₄ alkylene)-heteroaryl, —O—(C₁-C₄ alkylene)-aryl, —O—(C₁-C₄alkylene)-heteroaryl, —O—(C₁-C₄ alkylene)-heterocyclyl, —N(R⁷)-aryl, or—N(R⁷)-heteroaryl, wherein:

-   -   at least one of R^(1a) and R^(1b) is not hydrogen or methyl;    -   any alkylene moiety present in R^(1a) or R^(1b) is optionally        substituted with OH or F;    -   each R⁷ is independently selected from hydrogen and C₁-C₄ alkyl;        and    -   any aryl, heteroaryl, or hetercylyl of R^(1a) or R^(1b) is        optionally substituted with one or more substituents selected        from -G-L-M, halo, C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃;

G is a bond or a bivalent C₁-C₆ saturated or unsaturated, straight orbranched hydrocarbon chain wherein optionally one, two or threemethylene units of the hydrocarbon chain are independently replaced by—NR⁸—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—,—C(═NR⁸)—, —N═N—, or —C(═N₂)—;

-   -   L is a covalent bond or a bivalent C₁₋₈ saturated or        unsaturated, straight or branched, hydrocarbon chain, wherein        one, two, or three methylene units of L are optionally and        independently replaced by cyclopropylene, —NR⁸—, —N(R⁸)C(O)—,        —C(O)N(R⁸)—, —N(R⁸)SO₂—, SO₂N(R⁸)—, —O—, —C(O)—, —OC(O)—,        —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR⁸)—, —N═N—, or        —C(═N₂)—; M is E, or a 3-10 membered monocyclic or bicyclic,        saturated, partially unsaturated, or aromatic ring having 0-3        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, and wherein said ring is substituted with at 1-4 groups        independently selected from -D-E, oxo, NO₂, halogen, CN, C₁-C₆        alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

D is a covalent bond or a bivalent C₁-C₆ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one or two methyleneunits of D are optionally and independently replaced by —NR⁸—, —S—, —O—,—C(O)—, —SO—, or —SO₂—;

E is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinsaid alkyl, alkenyl or alkynyl is optionally substituted with oxo,halogen, or CN; and

each R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or an optionally substituted group selected from phenyl, a 4-7membered heterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

R² is selected from phenyl, a 3-7 membered cycloalkyl, and C₂-C₄ alkyl,wherein the phenyl or cycloalkyl is optionally substituted with asubstituent selected from methyl or fluoro;

each R³ is independently selected from —C₁-C₄ alkyl, —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), —C₁-C₄ fluoroalkyl, —C(O)—O—(C₁-C₄ alkyl),-phenyl, -heteroaryl, C₃-C₇ cycloalkyl, —CH₂—N(C₁-C₄ alkyl)₂,C(O)—N—(C₁-C₄ alkyl)₂, and —C(O)—NH—(C₁-C₄ alkyl), or

or two R³s are taken together to form a 3-8 saturated ring or a fusedphenyl wherein said saturated ring or fused phenyl is optionallysubstituted with 1 to 2 methyl groups;

R⁴ is selected from hydrogen, —CN, halo, C₁-C₄ alkoxy, —CH₂NH(C₁-C₄alkyl), C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl),C₁-C₄ fluoroalkyl, C(O)—N—(C₁-C₄ alkyl)₂, —C(O)—NH—(C₁-C₄ alkyl),—C(O)—O—(C₁-C₄ alkyl), —C(O)—OH, —S(O)₂—(C₁-C₄ alkyl), and a 5-memberedheteroaryl;

R⁵ is selected from: —C(O)—(C₁-C₄alkyl), —C(O)—(CH₂)₀₋₂-Q,—C(O)—(CH₂)₀₋₂—N(R⁶)—(CH₂)₀₋₂-Q, —C(O)—O—(CH₂)₁₋₂-Q,—C(O)—(CH₂)₁₋₂—O—(CH₂)₀₋₂-Q, —C(O)—C(O)-Q, —S(O)₂-Q, —C(O)—(C₁-C₄alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)—O—(C₁-C₄alkyl), —C(O)—N(R⁶)—(C₁-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl),—C(O)—N(R⁶)—(C₁-C₄ alkylene)-C(O)—O—(C₁-C₄ alkyl),—C(O)—(CH₂)₀₋₂—N(R⁶)—(C₁-C₆ alkyl), —C(O)—(CH₂)₀₋₂—N(R⁶)—(C₂-C₆alkynyl), —C(O)—(CH₂)₀₋₂—N(R⁶)—(C₂-C₆ alkenyl),—C(O)—(CH₂)₀₋₂—N(R⁶)—(CH₂)₀₋₂—O—(C₁-C₄ alkyl), —C(O)—(CH₂)₁₋₂—O—(C₁-C₄alkyl), —C(O)—O—(C₁-C₄ alkylene)-O—(C₁-C₄ alkyl), —(CH₂)₀₄—O—C(O)—(C₁-C₄alkyl), —(CH₂)₀₋₄—C(O)—O—(C₁-C₄ alkyl), —(CH₂)₀₋₄—O—(C₁-C₄ alkyl),—C(O)—(CH₂)₁₋₂—S—(C₁-C₄ alkyl), —S(O)₂—(C₁-C₄ alkyl), —C(O)—(C₁-C₄alkylene)-C(O)C(O)N(R⁶)(C₁-C₆ alkyl), —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂—(C₁-C₆ alkyl), and —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂Q, wherein:

-   -   any alkylene moiety present in R⁵ is optionally substituted with        OH or F;    -   any terminal methyl moiety present in R⁵ is optionally replaced        with —CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, or C(O)CF₃;

each R⁶ is independently selected from hydrogen and methyl;

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl,wherein Q is optionally substituted with up to 3 substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, —CN, fluoro,chloro, and bromo; and

m is 0, 1, 2 or 3.

In some embodiments, m is 0, 1 or 2; and each R³, if present, isindependently selected from methyl, ethyl, CF₃, isopropyl, cyclopropyland phenyl. In some embodiments, R³ is methyl or cyclopropyl. In someembodiments, R³ is methyl. In some embodiments, R³ is cyclopropyl.

In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, m is 1 and R³ is C₃₋₇ cycloalkyl (e.g.,cyclopropyl). In some embodiments, m is 1 and R³ is C₁-C₄ (alkyl) (e.g.,methyl or isopropyl). In some embodiments, m is 1 and R³ is haloalkyl(e.g., C₁-C₄ fluoroalkyl, e.g., CF₃). In some embodiments, m is 2, oneR³ is C₁₋₄ alkyl (e.g., methyl) and the other R³ is halo (e.g., fluoro).

In some embodiments, R⁴ is —CN or —C(O)—O—(C₁-C₄ alkyl). In someembodiments, R⁴ is CN.

In some embodiments, R⁴ is:

In some embodiments, R⁴ is

In some embodiments, Y is —N(R₅)—CH₂— or —CH₂—N(R⁵)—; R⁵ is —C(O)-Q andQ is cyclopropyl.

In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)R¹⁰; and R¹⁰ is selectedfrom heteroaryl, aryl, —CH₂-aryl, —CH₂-heteroaryl, and —(CH₂)₂—O—CH₃,wherein any aryl or heteroaryl portion of R⁸ is optionally substitutedwith methyl.

In some embodiments, Y is —N(R⁵)—; R⁵ is selected from selected from:—C(O)—(C₁-C₅ alkyl), —C(O)—(C₂-C₆ alkenyl), —C(O)—(C₀-C₂ alkylene)-Q,—C(O)—(C₁-C₄ alkenylene)-Q, —C(O)-(C₀-C₂ alkylene)-N(R⁶)—(C₀-C₂alkylene)-Q, —C(O)—(C₁-C₂ alkylene)-O—(C₀-C₂ alkylene)-Q, —C(O)—(C₁-C₄alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)—O—(C₁-C₄alkyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₁-C₆ alkyl), —C(O)—(C₀-C₂alkylene)N(R⁶)—(C₂-C₆ alkynyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₂-C₆alkenyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₀-C₂ alkylene)-O—(C₁-C₄ alkyl),—(C₀ alkylene)-C(O)O—(C₁-C₄ alkyl), —C(O)—(C₁-C₂ alkylene)-O—(C₁-C₄alkyl), —C(O)—(C₁-C₂ alkylene)-C(O)C(O)N(R)(C₁-C₄ alkyl), or—C(O)—(C₁-C₄ alkylene)-C(O)C(O)N(R⁶)(C₁-C₆ alkyl), wherein:

-   -   any alkylene moiety present in R⁵ is optionally substituted with        OCH₃, OH or F;    -   any terminal methyl moiety present in R⁵ is optionally replaced        with —CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, C(O)CF₃, CN, —OCH₃,        —C(O)H, —OP(O)(OH)₂, —OP(O)(C₁-C₄ alkoxy)₂ or CO₂H;

each R⁶ is independently selected from hydrogen and methyl;

-   -   Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl,        pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or        cyclopentyl, wherein each member of Q is optionally substituted        with up to 3 substituents independently selected from C₁-C₄        alkyl optionally substituted with OH, C₁-C₄ alkoxy,        —C(O)O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy), —CN,        —OH, fluoro, chloro, and bromo.

In some embodiments, Y is —N(R⁵)—; and R⁵ is —C(O)—(C₁-C₃alkyl)-O—(C₁-C₂ alkyl), —C(O)-Q, —C(O)—(C₁-C₅ alkyl), —C(O)—(C₁-C₂alkylene)-Q, —C(O)—(C₂-C₄ alkenyl), —C(O)O—(C₁-C₄ alkyl), or—C(O)—(C₁-C₄ alkenylene)-Q; wherein: any alkylene moiety present in R⁵is optionally substituted with OH; any terminal methyl moiety present inR⁵ is optionally replaced with —OH, CF₃, OCH₃, —C(O)H, OP(O)(C₁-C₄alkoxy)₂, or —OP(O)(OH)₂ (or a salt thereof, such as a sodium salt); Qis cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl,pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl,wherein each member of Q is optionally substituted with one substituentindependently selected from C₁-C₄ alkyl optionally substituted with OH,C₁-C₄ alkoxy, —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy), and —OH.

In some embodiments, Y is —N(R⁵)—; and R⁵ is —C(O)—(C₁-C₃alkyl)-O—(C₁-C₂ alkyl). In some embodiments, Y is —N(R⁵)—; and R⁵ is—C(O)—(CH₂)₂—OCH₃. In some embodiments, Y is —N(R⁵)— and R⁵ is—C(O)—(C₁-C₃ alkyl)-CF₃. In some embodiments, Y is —N(R⁵)— and R⁵ is—C(O)—CH₂—CF₃. In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)-Q and Q iscyclopropyl, oxetanyl or furanyl. In some embodiments, Y is —N(R⁵)— andR⁵ is —C(O)—CH₂—CH₂OH. In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)-Qwhere Q is substituted with C₁₋₄ alkoxy. In some embodiments, Y is—N(R⁵)— and R⁵ is —C(O)-cyclopropyl substituted with C₁₋₄ alkoxy (e.g.,ethoxy). In some embodiments, Y is —N(R⁵)— and R⁵ is —C(O)—OCH₃. In someembodiments, Y is —N(R⁵)— and R⁵—C(O)-Q where Q is substituted with(C₁₋₄ alkylene)-OCH₃. In some embodiments, Y is —N(R⁵)— andR⁵—C(O)-cyclopropyl substituted with CH₂OCH₃. In some embodiments, Y is—N(R⁵)— and R⁵—C(O)-Q where Q is substituted with C₁₋₄ alkyl whereinalkyl is optionally substituted with —OH. In some embodiments, Y is—N(R⁵)— and R⁵—C(O)-cyclopropyl substituted with CH₂OH. In someembodiments, Y is —N(R⁵)—; R⁵ is —C(O)-Q where Q is substituted with OH.In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)-cyclopropyl substitutedwith OH. In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)—(C₁₋₄ alkyl)-OH.In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)—CH₂C(OH)(CH₃)₂. In someembodiments, Y is —N(R⁵)—; R⁵ is —C(O)—CH₂CH(OH)CH₃. In someembodiments, Y is —N(R⁵)—; R⁵ is —C(O)—CH₂CH₂CH₂OH. In some embodiments,Y is —N(R⁵)—; R⁵ is —C(O)—CH₂CH₂OH. In some embodiments, Y is —N(R⁵)—;and R⁵ is —C(O)—(C₁-C₄ alkyl). In some embodiments, Y is —N(R⁵)—; and R⁵is —C(O)—CH₃. In some embodiments, Y is —N(R⁵)—; R⁵ is —C(O)—(C₁₋₄alkyl)-(OCH₃)₂. In some embodiments, Y is —N(R⁵)—; R⁵ is—C(O)—CH₂CH₂C(H)(OCH₃)₂. In some embodiments, Y is —N(R⁵)—; R⁵ is—C(O)—(C₁₋₄ alkyl)-C(O)H. In some embodiments, Y is —N(R⁵)—; R⁵ is—C(O)—CH₂CH₂C(O)H. In some embodiments, Y is —N(R⁵)—; R⁵ is—C(O)—C(cyclopropyl)(OH). In some embodiments, Y is —N(R⁵)—; R⁵ is—C(O)—(C₁₋₄ alkyl)-C(O)OCH₃. In some embodiments, Y is —N(R⁵)—; R⁵ is—C(O)—CH₂CH₂C(O)OCH₃. In some embodiments, Y is —N(R⁵)— and R⁵ is—C(O)—(C₀-C₂ alkylene)-Q. In some embodiments, Y is —N(R⁵)— and R⁵ is—C(O)—(C₀-C₂ alkylene)-Q, where Q is cyclopropyl, cyclobutyl, oxetanyl,furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl,dihydrofuranonyl, or cyclopentyl. In some embodiments, Y is —N(R⁵)— andR⁵ is —C(O)—CH₂-oxetanyl, —C(O)—CH₂-azetidinonyl,—C(O)—CH₂-pyrrolidinonyl, —C(O)—CH₂-cyclobutyl, —C(O)—CH₂-cyclopropyl,—C(O)—CH₂CH₂-cyclopropyl, —C(O)—CH₂-tetrahydrofuranyl,—C(O)—CH₂-dihydrofuranone, —C(O)—CH₂CH₂-oxetanyl, —C(O)—CH₂CH₂-furanyl,—C(O)—CH₂-ietrahydrofuranyl, —C(O)—CH₂CH₂-tetrahydrofuranyl or—C(O)—CH₂-cyclopentyl. In some embodiments, Y is —N(R⁵)— and R⁵ is—C(O)—(C₂-C₄ alkenyl)-OH. In some embodiments, Y is —N(R⁵)— and R⁵ is—C(O)—CH═CH—CH₂CH₂OH. In some embodiments, Y is —N(R⁵)— and R⁵—(C₀-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl). In some embodiments, Y is —N(R⁵)— andR⁵—C(O)—O-(t-butyl). In some embodiments, Y is —N(R⁵)— andR⁵—C(O)—(C₁-C₄ alkyl)-OP(O)(C₁-C₄ alkoxy)₂. In some embodiments, Y is—N(R⁵)— and R⁵—C(O)—CH₂CH₂CH₂—OP(O)(t-butoxy)₂. In some embodiments, Yis —N(R⁵)— and R⁵—C(O)—(C₁-C₄ alkyl)-OP(O)(OH)₂ or a salt thereof, suchas a sodium salt. In some embodiments, Y is —N(R⁵)— andR⁵—C(O)—CH₂CH₂—OP(O)(t-butoxy)₂. In some embodiments, Y is —N(R⁵)—; andR⁵ is —C(O)—(C₁-C₅ alkyl). In some embodiments, Y is —N(R⁵)—; and R⁵ is—C(O)-pentyl. In some embodiments, Y is —N(R⁵)—; and R⁵—C(O)—(C₁-C₄alkenylene)-Q. In some embodiments, Y is —N(R⁵)—; andR⁵—C(O)—CH=cyclobutyl.

In some embodiments, one of R^(1a) or R^(1b) is selected from hydrogenand methyl; and the other of R^(1a) or R^(1b) is selected fromisopropyl, —N(CH₃)—(CH₂)₂—NH—CH₃, aryl, heteroaryl, —CH₂-aryl,—CH₂-heteroaryl, —O—CH₂-aryl, and —O—CH₂-heteroaryl; wherein any aryl orheteroaryl of R^(1a) or R^(1b) is optionally substituted with one ormore substituents independently selected from alkoxy, OH, halo, C₁-C₆alkyl, —CF₃, CN, —OC(O)CH₃, and —OCF₃.

In some embodiments, one of R^(1a) or R^(1b) is selected from hydrogenand methyl; and the other of R^(1a) or R^(1b) is selected from aryl,heteroaryl, heterocyclyl, —(C₁-C₄ alkylene)-aryl, —(C₁-C₄alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-aryl, —O—(C₀-C₄alkylene)-heteroaryl, —N(R⁷)-aryl, —N(R⁷)heteroaryl, —N(R⁹)-aryl, or—N(R⁹)-heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl issubstituted with -G-L-M, CH₃, CN, alkoxy, OH, halo, C₁-C₆ alkyl, —CF₃,—OC(O)CH₃, or —OCF₃.

In some embodiments, one of R^(1a) or R^(1b) is selected from hydrogenand methyl; and the other of R^(1a) or R^(1b) is selected from aryl,heteroaryl, heterocyclyl, —(C₁-C₄ alkylene)-aryl, —(C₁-C₄alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-aryl, —O—(C₀-C₄alkylene)-heteroaryl, —N(R⁷)-aryl, —N(R⁷)heteroaryl, —N(R⁹)-aryl, or—N(R⁹)-heteroaryl, wherein said aryl or heteroaryl is substituted with-G-L-M, CH₃, or CN.

In some embodiments, R^(1a) is H and R^(1b) is aryl, heteroaryl,heterocyclyl, —(C₁-C₄ alkylene)-aryl, —(C₁-C₄ alkylene)-heteroaryl,—O—(C₀-C₄ alkylene)-aryl, or —O—(C₀-C₄ alkylene)-heteroaryl,—N(R⁷)-aryl, —N(R⁷)heteroaryl, —N(R⁹)-aryl, —N(R⁹)-heteroaryl, whereinsaid aryl or heteroaryl is substituted with -G-L-M, CH₃, or CN. In someaspects of the preceding embodiments, R^(1a) is H and R^(1b) is aryl,heteroaryl, heterocyclyl, —CH₂-aryl, —CH₂-heteroaryl, -D-aryl,—O-heteroaryl, —O—(CH₂)-aryl, —O—CH(CH₃)-aryl, —O(CH)(C(CH₃)₂)-aryl,—O—CH(CH₂CH₃)-aryl, —NH-aryl, —NH-heteroaryl, —N(CH₃)-aryl,—N(CH₃)-heteroaryl, —N(aryl)-aryl, —N(heteroaryl)-heteroaryl,—O—(CH₂)-heteroaryl or —O—CH(CH₃)-heteroaryl, wherein aryl is phenyl,heteroaryl is pyridyl, pyrimidinyl, naphthyridinyl, quinolyl,isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl,benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl,imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl,and heterocyclyl is benzodioxole, pyridazinone, benzoxazolone,indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone,tetrahydropyridinyl, dihydropyrrolyl and said phenyl, pyridyl,pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl,benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl,pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl,imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl,benzodioxole, pyridazinone, benzoxazolone, indolinone,N-methylindolinone, piperazinyl, N-methylisoquinolinone,tetrahydropyridinyl, or dihydropyrrolyl is substituted with -G-L-M,—CF₃, —OCF₃, halo (e.g., fluoro, chloro or bromo), CH₃, or CN.

In some embodiments, R^(1a) is methyl and R^(1b) is aryl, heteroaryl,heterocyclyl, —O—(C₀-C₄ alkylene)-aryl, or —O—(C₀-C₄alkylene)-heteroaryl, wherein said aryl or heteroaryl is substitutedwith -G-L-M, CH₃, or CN. In some aspects of the preceding embodiments,R^(1a) is methyl or H and R^(1b) is aryl, heteroaryl, heterocyclyl,—O—(CH₂)-aryl, —O—CH(CH₃)-aryl, —O—(CH₂)-heteroaryl or—O—CH(CH₃)-heteroaryl, wherein aryl is phenyl or naphthyl and heteroarylis quinolinyl, pyrazolyl, isoquinolinyl, pyridyl, pyrimidinyl, indolyl,or pyrazolyl, and heterocyclyl is tetrahydropyridinyl and said phenyl,pyridyl, pyrimidinyl, indolyl, or pyrazolyl is substituted with -G-L-M,halo (e.g., chloro or fluoro), CH₃, or CN.

In some embodiments, -G-L-M is:

C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, hydrogen, tetrazolyl,morpholino, piperazinyl, pyrrolidinone, pyrazolyl, benzyl, —(CH₂)₁₋₄—SH,—(CH₂)₁₋₄—NH₂, —NH₂, —(CH₂)₁₋₄—OH, —N(H)C(O)OCH(CH₃)₃, —(CH₂)₁₋₄—OCH₃,—NH—(CH₂)₁₋₄—OH, —C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkenyl),—O—(CH₂)₁₋₄—C(O)—O—(C₁-C₄ alkyl), —C(O)NH₂, —(CH₂)₁₋₄C(O)CH₃,—N(CH₃)(CH₃), —NHC(O)(C₂-C₄ alkenyl), —NHC(O)(C₂-C₄ alkyl),—SO₂(CH₂)₁₋₄, —(CH₂)₁₋₄—NHSO₂Me, —NHSO₂(CH₂)₁₋₄, —O—SO₂CF₃,—SO₂NH—(C₁-C₄ alkyl), —SO₂NH—(C₂-C₄ alkenyl), SO₂—NH₂ or —NHSO₂Me.

In some embodiments, R² is selected from isopropyl, cyclopropyl,cyclohexyl, and phenyl. In some embodiments, R² is cyclopropyl. In someembodiments, R₂ is isopropyl.

In some embodiments, R⁴ is CN; Y is —N(R⁵)—; R⁵ is —C(O)R¹⁰; and thecompound has Structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

one of R^(1a) or R^(1b) is selected from hydrogen and methyl;

the other of R^(1a) or R^(1b) is selected from aryl, heteroaryl,heterocyclyl, —(C₁-C₄ alkylene)-aryl, —(C₁-C₄ alkylene)-heteroaryl,—O—(C₀-C₄ alkylene)-aryl, —O—(C₀-C₄ alkylene)-heteroaryl, —N(R⁷)-aryl,—N(R⁷)heteroaryl, —N(R⁹)-aryl, or —N(R⁹)-heteroaryl, wherein said aryl,heterocyclyl, or heteroaryl is substituted with -G-L-M, CH₃, CN, alkoxy,OH, halo, C₁-C₆ alkyl, —CF₃, —OC(O)CH₃, or —OCF₃;

R² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;

each R³, if present, is selected from methyl, ethyl, isopropyl, CF₃,cyclopropyl and phenyl;

R¹⁰ is selected from —(C₁-C₃ alkyl)-O—(C₁-C₂ alkyl), Q, (C₁-C₅ alkyl),C₁-C₂ alkylene)-Q, (C₂-C₄ alkenyl), —O—(C₁-C₄ alkyl), or —(C₁-C₄alkenylene)-Q; wherein: any alkylene moiety present in R¹⁰ is optionallysubstituted with OH; any terminal methyl moiety present in R¹⁰ isoptionally replaced with —OH, CF₃, OCH₃, —C(O)H, —OP(O)(C₁-C₄ alkoxy)₂,or —OP(O)(OH)₂ (or a salt thereof, such as a sodium salt); Q iscyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl,pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl,wherein each member of Q is optionally substituted with one substituentindependently selected from C₁-C₄ alkyl optionally substituted with OH,C₁-C₄ alkoxy, —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy), and —OH; and

m is 0, 1, or 2.

In certain embodiments, m is 1; and the compound has Structural FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is hydrogen or methyl;

R^(1b) is selected from aryl, heteroaryl, heterocyclyl, —(C₁-C₄alkylene)-aryl, —(C₁-C₄ alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-aryl,—O—(C₀-C₄ alkylene)-heteroaryl, —N(R⁷)-aryl, —N(R⁷)heteroaryl,—N(R⁹)-aryl, or —N(R⁹)-heteroaryl, wherein said aryl, heterocyclyl, orheteroaryl is substituted with -G-L-M, CH₃, CN, alkoxy, OH, halo, C₁-C₆alkyl, —CF₃, —OC(O)CH₃, or —OCF₃;

R² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;

each R³, if present, is selected from methyl, isopropyl, andcyclopropyl;

R¹⁰ is selected from —(C₁-C₃ alkyl)-O—(C₁-C₂ alkyl), Q, (C₁-C₅ alkyl),C₁-C₂ alkylene)-Q, (C₂-C₄ alkenyl), —O—(C₁-C₄ alkyl), or —(C₁-C₄alkenylene)-Q; wherein: any alkylene moiety present in R¹⁰ is optionallysubstituted with OH; any terminal methyl moiety present in R¹⁰ isoptionally replaced with —OH, CF₃, OCH₃, —C(O)H, —OP(O)(C₁-C₄ alkoxy)₂,or —OP(O)(OH)₂ (or a salt thereof, such as a sodium salt); Q iscyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl,pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl,wherein each member of Q is optionally substituted with one substituentindependently selected from C₁-C₄ alkyl optionally substituted with OH,C₁-C₄ alkoxy, —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy), and —OH; and

m is 0, 1, or 2.

In some embodiments, R⁴ is CN; Y is —N(R⁵)—; R⁵ is —C(O)R¹⁰; and thecompound has Structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

one of R^(1a) or R^(1b) is selected from hydrogen and methyl;

the other of R^(1a) or R^(1b) is selected from isopropyl,—N(CH₃)—(CH₂)₂—NH—CH₃, aryl, heteroaryl, —CH₂-aryl, —CH₂-heteroaryl,—O—CH₂-aryl, and —O—CH₂-heteroaryl; wherein any aryl or heteroarylportion of R^(1a) or R^(1b) is optionally substituted with one or moresubstituents independently selected from alkoxy, hydroxy, halo, C₁-C₆alkyl, —CF₃, —OC(O)CH₃, and —OCF₃;

R² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;

each R³, if present, is selected from methyl, ethyl, isopropyl,cyclopropyl and phenyl;

R¹⁰ is selected from heteroaryl, aryl, —CH₂-aryl, —CH₂-heteroaryl, and—(CH₂)₂—O—CH₃, wherein any aryl or heteroaryl portion of R¹⁰ isoptionally substituted with methyl; and

m is 0, 1, or 2.

In certain embodiments, m is 1; and the compound has Structural FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is selected from hydrogen and methyl;

R^(1b) is selected from aryl, and heteroaryl; wherein the aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from methoxy, fluoro, chloro, methyl, —CF₃,—OCF₃;

R² is selected from isopropyl and cyclopropyl;

R³ is selected from methyl, ethyl, isopropyl and cyclopropyl; and

R¹⁰ is selected from —(CH₂)₂—O—CH₃, furan-3-yl, 2-methylfuran-3-yl andthien-2-yl.

In some embodiments, R⁴ is CN; Y is —N(R⁵)—; R⁵ is —C(O)R¹⁰; and thecompound has Structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is H;

R^(1b) is aryl, heteroaryl, —O—(C₁-C₄ alkylene)-aryl, or —O—(C₁-C₄alkylene)-heteroaryl, wherein said aryl or heteroaryl is substitutedwith -G-L-M, CH₃, or CN;

R² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;

each R³, if present, is selected from methyl, ethyl, isopropyl,cyclopropyl and phenyl;

R¹⁰ is selected from heteroaryl, aryl, —CH₂-aryl, —CH₂-heteroaryl, and—(CH₂)₂—O—CH₃, wherein any aryl or heteroaryl portion of R¹⁰ isoptionally substituted with methyl; and

m is 0, 1, or 2.

In certain embodiments, m is 1; and the compound has Structural FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is H;

R^(1b) is aryl, heteroaryl, —O—(CH₂)-aryl, —O—CH(CH₃)-aryl,—O—(CH₂)-heteroaryl or —O—CH(CH₃)-heteroaryl, wherein aryl is phenyl andheteroaryl is pyridyl, pyrimidinyl, indolyl, or pyrazolyl, and saidphenyl, pyridyl, pyrimidinyl, indolyl or pyrazolyl is substituted with-G-L-M, CH₃, or CN;

R² is selected from isopropyl and cyclopropyl;

R³ is selected from methyl, ethyl, isopropyl and cyclopropyl; and

R¹⁰ is selected from —(CH₂)₂—O—CH₃, furan-3-yl, 2-methylfuran-3-yl andthien-2-yl.

In another embodiment, the compound is selected from any one of thecompounds set forth in Table 1, below.

TABLE 1 Exemplary Compounds of Formula I. Cmpd No. Structure 100

101

102

103

104

105

106

107

108

109

110

111

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

187

188

189

190

191

192

193

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

 59

 60

 61

In another embodiment, the compound is selected from any one of thecompounds set forth in Table 5, below.

TABLE 5 Exemplary Compounds of Formula I. Cpd # Structure 263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

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589

590

591

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599

600

601

602

603

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609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

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626

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629

630

631

632

633

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635

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638

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641

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650

651

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661

662

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664

665

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668

669

670

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675

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679

680

681

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683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707 708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

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745

746

747

748

749

750

751

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764

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766

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769

770

771

772

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781

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784

785

786

787

788

789

790

791

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795

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799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates, racemic mixtures, scalemicmixtures, and diastereomeric mixtures, as well as single enantiomers orindividual stereoisomers that are substantially free from anotherpossible enantiomer or stereoisomer. The term “substantially free ofother stereoisomers” as used herein means a preparation enriched in acompound having a selected stereochemistry at one or more selectedstereocenters by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,96%, 97%, 98%, or 99%. The term “enriched” means that at least thedesignated percentage of a preparation is the compound having a selectedstereochemistry at one or more selected stereocenters. Methods ofobtaining or synthesizing an individual enantiomer or stereoisomer for agiven compound are known in the art and may be applied as practicable tofinal compounds or to starting material or intermediates.

The compounds of Formula I, II and IIa may also comprise one or moreisotopic substitutions. For example, H may be in any isotopic form,including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may be inany isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise indicated when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The compounds of this invention may also be represented in multipletautomeric forms, in such instances, the invention expressly includesall tautomeric forms of the compounds described herein, even though onlya single tautomeric form may be represented (e.g., alkylation of a ringsystem may result in alkylation at multiple sites, the inventionexpressly includes all such reaction products). All such isomeric formsof such compounds are expressly included in the present invention. Allcrystal forms of the compounds described herein are expressly includedin the present invention.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO), then a salt may be formed witha suitable cation. Examples of suitable inorganic cations include, butare not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺. Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R²⁺,NHR³⁺, NR⁺). Examples of some suitable substituted ammonium ions arethose derived from: ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine andarginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group that may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound alsoincludes salt forms thereof.

Compositions and Routes of Administration

The compounds utilized in the methods described herein may be formulatedtogether with a pharmaceutically acceptable carrier or adjuvant intopharmaceutically acceptable compositions prior to be administered to asubject. In another embodiment, such pharmaceutically acceptablecompositions further comprise additional therapeutic agents in amountseffective for achieving a modulation of disease or disease symptoms,including those described herein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a subject, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vCompound AGInally or via an implanted reservoir, preferablyby oral administration or administration by injection. Thepharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleCompound AGlnous suspension. This suspension may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents (such as, for example, Tween 80) and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are mannitol,water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil may beemployed including synthetic mono- or diglycerides. Fatty acids, such asoleic acid and its glyceride derivatives are useful in the preparationof injectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, or carboxymethyl cellulose or similar dispersingagents which are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is useful when the desired treatment involves areas or organsreadily accessible by topical application. For application topically tothe skin, the pharmaceutical composition should be formulated with asuitable ointment containing the active components suspended ordissolved in a carrier. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of this invention may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. When the compositions of this invention comprise a combinationof a compound of the formulae described herein and one or moreadditional therapeutic or prophylactic agents, both the compound and theadditional agent should be present at dosage levels of between about 1to 100%, and more preferably between about 5 to 95% of the dosagenormally administered in a monotherapy regimen. The additional agentsmay be administered separately, as part of a multiple dose regimen, fromthe compounds of this invention. Alternatively, those agents may be partof a single dosage form, mixed together with the compounds of thisinvention in a single composition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparationscontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular subject will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the subject'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Subjects may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

The pharmaceutical compositions described above comprising a compound ofStructural Formula I, II or IIa or a compound described in any one ofthe embodiments herein, may further comprise another therapeutic agentuseful for treating cancer.

Methods of Use

Provided is a method for inhibiting a mutant IDH1 activity comprisingcontacting a subject in need thereof a compound of Structural Formula I,II or IIa, a compound described in any one of the embodiments herein, ora pharmaceutically acceptable salt thereof. In one embodiment, thecancer to be treated is characterized by a mutant allele of IDH1 whereinthe IDH1 mutation result in a new ability of the enzyme to catalyze theNAPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutaratein a subject. In one aspect of this embodiment, the mutant IDH1 has anR132X mutation. In one aspect of this embodiment, the R132X mutation isselected from R132H, R132C, R132L, R132V, R132S and R132G. In anotheraspect, the R132X mutation is R132H or R132C. In yet another aspect, theR132X mutation is R132H.

Also provided are methods of treating a cancer characterized by thepresence of a mutant allele of IDH1 comprising the step of administeringto subject in need thereof (a) a compound of Structural Formula I, II orIIa, a compound described in any one of the embodiments herein, or apharmaceutically acceptable salt thereof, or (b) a pharmaceuticalcomposition comprising (a) and a pharmaceutically acceptable carrier.

In one embodiment, the cancer to be treated is characterized by a mutantallele of IDH1 wherein the IDH1 mutation result in a new ability of theenzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate toR(−)-2-hydroxyglutarate in a patient. In one aspect of this embodiment,the IDH1 mutation is an R132X mutation. In another aspect of thisembodiment, the R132X mutation is selected from R132H, R132C, R132L,R132V, R132S and R132G. In another aspect, the R132X mutation is R132Hor R132C. A cancer can be analyzed by sequencing cell samples todetermine the presence and specific nature of (e.g., the changed aminoacid present at) a mutation at amino acid 132 of IDH1.

Without being bound by theory, applicants believe that mutant alleles ofIDH1 wherein the IDH1 mutation result in a new ability of the enzyme tocatalyze the NAPH-dependent reduction of α-ketoglutarate toR(−)-2-hydroxyglutarate, and in particular R132H mutations of IDH1,characterize a subset of all types of cancers, without regard to theircellular nature or location in the body. Thus, the compounds and methodsof this invention are useful to treat any type of cancer that ischaracterized by the presence of a mutant allele of IDH1 imparting suchactivity and in particular an IDH1 R132H or R132C mutation.

In one aspect of this embodiment, the efficacy of cancer treatment ismonitored by measuring the levels of 2HG in the subject. Typicallylevels of 2HG are measured prior to treatment, wherein an elevated levelis indicative of the use of the compound of Formula I to treat thecancer. Once the elevated levels are established, the level of 2HG isdetermined during the course of and/or following termination oftreatment to establish efficacy. In certain embodiments, the level of2HG is only determined during the course of and/or following terminationof treatment. A reduction of 2HG levels during the course of treatmentand following treatment is indicative of efficacy. Similarly, adetermination that 2HG levels are not elevated during the course of orfollowing treatment is also indicative of efficacy. Typically, the these2HG measurements will be utilized together with other well-knowndeterminations of efficacy of cancer treatment, such as reduction innumber and size of tumors and/or other cancer-associated lesions,improvement in the general health of the subject, and alterations inother biomarkers that are associated with cancer treatment efficacy.

2HG can be detected in a sample by LC/MS. The sample is mixed 80:20 withmethanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degreesCelsius. The resulting supernatant can be collected and stored at −80degrees Celsius prior to LC-MS/MS to assess 2-hydroxyglutarate levels. Avariety of different liquid chromatography (LC) separation methods canbe used. Each method can be coupled by negative electrospray ionization(ESI, −3.0 kV) to triple-quadrupole mass spectrometers operating inmultiple reaction monitoring (MRM) mode, with MS parameters optimized oninfused metabolite standard solutions. Metabolites can be separated byreversed phase chromatography using 10 mM tributyl-amine as an ionpairing agent in the aqueous mobile phase, according to a variant of apreviously reported method (Luo et al. J Chromatogr A 1147, 153-64,2007). One method allows resolution of TCA metabolites: t=0, 50% B; t=5,95% B; t=7, 95% B; t=8, 0% B, where B refers to an organic mobile phaseof 100% methanol. Another method is specific for 2-hydroxyglutarate,running a fast linear gradient from 50%-95% B (buffers as defined above)over 5 minutes. A Synergi Hydro-RP, 100 mm×2 mm, 2.1 μm particle size(Phenomonex) can be used as the column, as described above. Metabolitescan be quantified by comparison of peak areas with pure metabolitestandards at known concentration. Metabolite flux studies from¹³C-glutamine can be performed as described, e.g., in Munger et al. NatBiotechnol 26, 1179-86, 2008.

In one embodiment 2HG is directly evaluated.

In another embodiment a derivative of 2HG formed in process ofperforming the analytic method is evaluated. By way of example such aderivative can be a derivative formed in MS analysis. Derivatives caninclude a salt adduct, e.g., a Na adduct, a hydration variant, or ahydration variant which is also a salt adduct, e.g., a Na adduct, e.g.,as formed in MS analysis.

In another embodiment a metabolic derivative of 2HG is evaluated.Examples include species that build up or are elevated, or reduced, as aresult of the presence of 2HG, such as glutarate or glutamate that willbe correlated to 2HG, e.g., R-2HG.

Exemplary 2HG derivatives include dehydrated derivatives such as thecompounds provided below or a salt adduct thereof:

In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60,70, 80 or 90% of the tumor cells carry an IDH1 mutation, and inparticular an IDH1 R132H or R132C mutation, at the time of diagnosis ortreatment.

IDH1 R132X mutations are known to occur in certain types of cancers asindicated in Table 2, below.

TABLE 2 IDH mutations associated with certain cancers IDH1 R132X CancerType Mutation Tumor Type brain tumors R132H primary tumor R132C primarytumor R132S primary tumor R132G primary tumor R132L primary tumor R132Vprimary tumor fibrosarcoma R132C HT1080 fibrosarcoma cell line AcuteMyeloid Leukemia R132H primary tumor (AML) R132G primary tumor R132Cprimary tumor Prostate cancer R132H primary tumor R132C primary tumorAcute lymphoblastic leukemia R132C primary tumor (ALL) paragangliomasR132C primary tumor

IDH1 R132H mutations have been identified in glioblastoma, acutemyelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer,cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS),myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblasticnon-Hodgkin's lymphoma (NHL). Accordingly, in one embodiment, themethods described herein are used to treat glioma (glioblastoma), acutemyelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer(NSCLC) or eholangiocarcinomas, chondrosarcoma, myelodysplasticsyndromes (MDS), myeloproliferative neoplasm (MPN) or colon cancer in apatient.

Accordingly in one embodiment, the cancer is a cancer selected from anyone of the cancer types listed in Table 2, and the IDH R132X mutation isone or more of the IDH1 R132X mutations listed in Table 2 for thatparticular cancer type.

Treatment methods described herein can additionally comprise variousevaluation steps prior to and/or following treatment with a compound ofStructural Formula I, II or IIa or a compound described in any one ofthe embodiments described herein.

In one embodiment, prior to and/or after treatment with a compound ofStructural Formula I, II or IIa or a compound described in any one ofthe embodiments described herein, the method further comprises the stepof evaluating the growth, size, weight, invasiveness, stage and/or otherphenotype of the cancer.

In one embodiment, prior to and/or after treatment with a compound offormula I or I-a or a compound described in any one of the embodimentsdescribed herein, the method further comprises the step of evaluatingthe IDH1 genotype of the cancer. This may be achieved by ordinarymethods in the art, such as DNA sequencing, immuno analysis, and/orevaluation of the presence, distribution or level of 2HG.

In one embodiment, prior to and/or after treatment with a compound offormula I or I-a or a compound described in any one of the embodimentsdescribed herein, the method further comprises the step of determiningthe 2HG level in the subject. This may be achieved by pectroscopicanalysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRSmeasurement, sample analysis of bodily fluid, such as serum or spinalcord fluid analysis, or by analysis of surgical material, e.g., bymass-spectroscopy.

Combination Therapies

In some embodiments, the methods described herein comprise theadditional step of co-administering to a subject in need thereof asecond therapy e.g., an additional cancer therapeutic agent or anadditional cancer treatment. Exemplary additional cancer therapeuticagents include for example, chemotherapy, targeted therapy, antibodytherapies, immunotherapy, and hormonal therapy. Additional cancertreatments include, for example: surgery, and radiation therapy.Examples of each of these treatments are provided below.

The term “co-administering” as used herein with respect to an additionalcancer therapeutic agents means that the additional cancer therapeuticagent may be administered together with a compound of this invention aspart of a single dosage form (such as a composition of this inventioncomprising a compound of the invention and an second therapeutic agentas described above) or as separate, multiple dosage forms.Alternatively, the additional cancer therapeutic agent may beadministered prior to, consecutively with, or following theadministration of a compound of this invention. In such combinationtherapy treatment, both the compounds of this invention and the secondtherapeutic agent(s) are administered by conventional methods. Theadministration of a composition of this invention, comprising both acompound of the invention and a second therapeutic agent, to a subjectdoes not preclude the separate administration of that same therapeuticagent, any other second therapeutic agent or any compound of thisinvention to said subject at another time during a course of treatment.The term “co-administering” as used herein with respect to an additionalcancer treatment means that the additional cancer treatment may occurprior to, consecutively with, concurrently with or following theadministration of a compound of this invention.

In some embodiments, the additional cancer therapeutic agent is achemotherapy agent. Examples of chemotherapeutic agents used in cancertherapy include, for example, antimetabolites (e.g., folic acid, purine,and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards,nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes,aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitorsand others) and hypomethylating agents (e.g., decitabine(5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine(5-azacytidine), 5-fluoro-2′-deoxycytidine, 5,6-dihydro-5-azacytidineand others). Exemplary agents include Aclarubicin, Actinomycin,Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,Amsacrine, Anagrelide, Arsenic trioxide, AsparCompound AGlnase,Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib,Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur,Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin,Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine,Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine,Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin,Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide,Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide,Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomaldoxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone,Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate,Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin,Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel,Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin,Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide,Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine,Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and othercytostatic or cytotoxic agents described herein.

Because some drugs work better together than alone, two or more drugsare often given at the same time. Often, two or more chemotherapy agentsare used as combination chemotherapy.

In some embodiments, the additional cancer therapeutic agent is adifferentiation agent. Such differentiation agent includes retinoids(such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid,13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR));arsenic trioxide; histone deacetylase inhibitors HDACs (such asazacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate));hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA));vitamin D; and cytokines (such as colony-stimulating factors includingG-CSF and GM-CSF, and interferons).

In some embodiments the additional cancer therapeutic agent is atargeted therapy agent. Targeted therapy constitutes the use of agentsspecific for the deregulated proteins of cancer cells. Small moleculetargeted therapy drugs are generally inhibitors of enzymatic domains onmutated, overexpressed, or otherwise critical proteins within the cancercell. Prominent examples are the tyrosine kinase inhibitors such asAxitinib, Bosutinib, Cediranib, aasatinib, erlotinib, imatinib,gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib,Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitorssuch as Alvocidib and Seliciclib. Monoclonal antibody therapy is anotherstrategy in which the therapeutic agent is an antibody whichspecifically binds to a protein on the surface of the cancer cells.Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®)typically used in breast cancer, and the anti-CD20 antibody rituximaband Tositumomab typically used in a variety of B-cell malignancies.Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab,Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusionproteins include Aflibercept and Denileukin diftitox. In someembodiments, the targeted therapy can be used in combination with acompound described herein, e.g., a biguanide such as metformin orphenformin, preferably phenformin.

Targeted therapy can also involve small peptides as “homing devices”which can bind to cell surface receptors or affected extracellularmatrix surrounding the tumor. Radionuclides which are attached to thesepeptides (e.g., RGDs) eventually kill the cancer cell if the nuclidedecays in the vicinity of the cell. An example of such therapy includesBEXXAR®.

In some embodiments, the additional cancer therapeutic agent is animmunotherapy agent. Cancer immunotherapy refers to a diverse set oftherapeutic strategies designed to induce the subject's own immunesystem to fight the tumor. Contemporary methods for generating an immuneresponse against tumors include intravesicular BCG immunotherapy forsuperficial bladder cancer, and use of interferons and other cytokinesto induce an immune response in renal cell carcinoma and melanomasubjects.

Allogeneic hematopoietic stem cell transplantation can be considered aform of immunotherapy, since the donor's immune cells will often attackthe tumor in a graft-versus-tumor effect. In some embodiments, theimmunotherapy agents can be used in combination with a compound orcomposition described herein.

In some embodiments, the additional cancer therapeutic agent is ahormonal therapy agent. The growth of some cancers can be inhibited byproviding or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostatecancers. Removing or blocking estrogen or testosterone is often animportant additional treatment. In certain cancers, administration ofhormone agonists, such as progestogens may be therapeuticallybeneficial. In some embodiments, the hormonal therapy agents can be usedin combination with a compound or a composition described herein.

Other possible additional therapeutic modalities include imatinib, genetherapy, peptide and dendritic cell vaccines, synthetic chlorotoxins,and radiolabeled drugs and antibodies.

EXAMPLES

ABBREVIATIONS anhy.—anhydrous aq.—aqueous min—minute(s) mL—millilitermmol—millimole(s) mol—mole(s) MS—mass spectrometry NMR—nuclear magneticresonance TLC—thin layer chromatography HPLC—high-performance liquidchromatography Hz—hertz δ—chemical shift J—coupling constant s—singletd—doublet t—triplet q—quartet m—multiplet br—broad qd—quartet ofdoublets dquin—doublet of quintets dd—doublet of doublets dt—doublet oftriplets CHCl₃—chloroform DCM—dichloromethane DMF—dimethylformamideEt₂O—diethyl ether EtOH—ethyl alcohol EtOAc—ethyl acetate MeOH—methylalcohol MeCN—acetonitrile PE—petroleum ether THF—tetrahydrofuranAcOH—acetic acid HCl—hydrochloric acid H₂SO₄—sulfuric acidNH₄Cl—ammonium chloride KOH—potassium hydroxide NaOH—sodium hydroxideK₂CO₃—potassium carbonate Na₂CO₃—sodium carbonate TFA—trifluoroaceticacid Na₂SO₄—sodium sulfate NaBH₄—sodium borohydride NaHCO₃—sodiumbicarbonate LiHMDS—lithium hexamethyldisilylamide NaHMDS—sodiumhexamethyldisilylamide LAH—lithium aluminum hydride NaBH₄—sodiumborohydride LDA—lithium diisopropylamide Et₃N—triethylamineDMAP—4-(dimethylamino)pyridine DIPEA—N,N-diisopropylethylamineNH₄OH—ammonium hydroxideEDCI—1-ethyl-3-(3-dimethylaminopropyl)carbodiimideHOBt—1-hydroxybenzotriazoleHATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetra-methyluroniumBINAP—2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl

In the following examples, reagents were purchased from commercialsources (including Alfa, Acros, Sigma Aldrich, TCI and Shanghai ChemicalReagent Company), and used without further purification. Flashchromatography was performed on an Ez Purifier III using a column withsilica gel particles of 200-300 mesh. Analytical and preparative thinlayer chromatography plates (TLC) were HSGF 254 (0.15-0.2 mm thickness,Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR)spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland).Chemical shifts were reported in parts per million (ppm, δ) downfieldfrom tetramethylsilane. Mass spectra were run with electrosprayionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA).HPLC chromatographs were recorded on an Compound AGIlent 1200 LiquidChromatography (Compound AGIlent, USA, column: Ultimate 4.6 mm×50 mm, 5μm, mobile phase A: 0.1% formic acid in water; mobile phase B:acetonitrile). Microwave reactions were run on an Initiator 2.5Microwave Synthesizer (Biotage, Sweden).

For exemplary compounds disclosed in this section, the specification ofa stereoisomer (e.g., an (R) or (S) stereoisomer) indicates apreparation of that compound such that the compound is enriched at thespecified stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or99%.

Example 1 Preparation of(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7, wherein R^(1a) is hydrogen; m is 1; R³ is 3-methyl; and R⁸ ismethoxyethyl) was prepared according to general Scheme 1, below.

Step A: 1-(dimethylamino)-4-methylpent-1-en-3-one (2)

To a solution of commerically available 3-methylbutan-2-one (1; 8.613 g,100 mmol) in 150 mL of anhydrous DMF was added commercially available1,1-dimethoxy-N,N-dimethylmethanamine (29.80 g, 250 mmol). The resultingmixture was stirred at 100° C. overnight. After removal of DMF andexcess of acetal, 14 g of title compound was obtained as a crude productand used in subsequent reaction without further purification. ¹H NMR(CHLOROFORM-d) δ 7.57 (d, J=12.8 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H),2.80-3.10 (m, 6H), 2.56 (dt, J=13.7, 6.8 Hz, 1H), 1.06-1.14 (m, 6H).

Step B: 6-isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3)

8.8 g of 1-(dimethylamino)-4-methylpent-1-en-3-one (2; 62 mmol) and 5.3g of commercially available cyanoacetamide (62 mmol) in 24 mL of H₂O wastreated with a premixed buffer solution of 0.7 mL of acetic acid, 1.8 mLof H₂O, and enough piperidine to make the buffer solution basic. Theresulting solution was refluxed for 2 hrs and LC-MS showed the formationof desired product. After cooling to room temperature, the mixture wasacidified with glacial acetic acid, and a brown yellowish precipitatewas formed. The filter cake was washed with H₂O and air-dried to give6.5 g of title compound. MS (ES) M+H expected 163.1, found 163.0. ¹H NMR(DMSO-d₆) δ 12.51 (br. s., 1H), 7.96-8.18 (m, 1H), 6.24 (d, J=7.5 Hz,1H), 2.83 (spt, J=6.9 Hz, 1H), 1.19 (s, 29H), 1.17 (s, 3H).

Step C: 5-bromo-6-isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (4)

To a solution of 2-hydroxy-6-isopropylnicotinonitrile (3; 3.0 g, 19mmol) in 50 mL of DCE was added NBS (5 g, 28 mmol) at room temperature.The reaction mixture was then heated at reflux for 3 hours. After LC-MSshowed the completion of reaction, the mixture was cooled to roomtemperature and poured into water and extracted with methylene chloride.The combined organic layer was dried over anhy. Na₂SO₄ and concentratedin vacuo. Column chromatography (4% MeOH/DCM) afforded 3.9 g of titlecompound as a brown solid. MS (ES) M+H expected 241.0, found 240.9. ¹HNMR (DMSO-d₆) δ 12.58 (br. s., 1H), 8.38 (s, 1H), 3.25-3.32 (m, 1H),1.23 (s, 3H), 1.21 (s, 3H).

Step D: 5-bromo-3-cyano-6-isopropylpyridin-2-yltrifluoromethanesulfonate (5)

To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (4; 2.0 g,8 mmol) in 20 mL of methylene chloride was added DMAP (100 mg, 0.8mmol), and triethylamine (1.01 g, 10 mmol). The mixture was cooled to 0°C. in an ice-water bath, and trifluoromethanesulfonic anhydride (2.82 g,10 mmol) was added dropwise by syringe. The resulting reaction mixturewas stirred at 0° C. for 30 min before it was allowed to warm to roomtemperature and stirred for additional 2 hours. After TLC showed thecomplete conversion of starting material to product, the reactionmixture was concentrated and purified by column chromatography (20%EtOAc/petroleum ether) to afford 2.8 g of title compound. ¹H NMR(CHLOROFORM-d) δ 8.22 (s, 1H), 3.57 (spt, J=6.7 Hz, 1H), 1.28 (d, J=6.8Hz, 6H).

Step E:(R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (6)

A mixture of the above triflate 5 (1.68 g, 4.5 mmol),(R)-2-methylpiperazine (770 mg, 6.77 mmol), and triethylamine (1.9 mL,13.5 mmol) suspended in 5 mL of MeCN was subjected to microwave reactionat 175° C. for 45 min. After the mixture was concentrated in vacuo, theresidue was purified by column chromatography (10% DCM/MeOH) to afford0.91 g of title compound as a light yellowish solid. MS (ES) M+Hexpected 323.1, found 323.0. ¹H NMR (CHLOROFORM-d) S 7.79 (s, 1H),4.35-4.40 (m, 0.5H), 4.32-4.35 (m, 1H), 4.30 (t, J=2.4 Hz, 0.5H),3.37-3.45 (m, 1H), 3.08-3.13 (m, 0.5H), 3.05-3.08 (m, 1H), 3.04 (d,J=2.5 Hz, 0.5H), 2.96-3.01 (m, 1H), 2.89-2.96 (m, 1H), 2.65-2.74 (m,1H), 1.21 (dd, J=6.8, 0.8 Hz, 6H), 1.13 (d, J=6.3 Hz, 3H).

Step F:(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7)

To a 25 mL of round-bottom flask was added(R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (6;680 mg, 2.1 mmol), 3-methoxypropanoic acid (438 mg, 4.2 mmol), HATU (1.6g, 4.2 mmol), DIPEA (1.1 mL, 6.31 mmol) and 5 mL of methylene chloride.The resulting reaction mixture was stirred at room temperature for 4hours until TLC showed the completion of the reaction. After washingwith Satd. NaHCO₃, brine, the combined organic layer was dried overanhy. Na₂SO₄ and concentrated in vacuo. Column chromatographypurification (20% EtOAc/petroleum ether) afforded 550 mg of titlecompound as a light yellowish solid. MS (ES) M+H expected 409.1, found409.0. ¹H NMR (CHLOROFORM-d) δ 7.83 (s, 1H), 4.90 (br. s., 0.5H), 4.52(d, J=12.3 Hz, 0.5H), 4.19-4.39 (m, 3H), 3.76-3.85 (m, 0.5H), 3.73 (t,J=6.4 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m, 1H),3.02-3.20 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.61 (m, 1H), 1.35 (d, J=7.0Hz, 1.5H), 1.25 (d, J=6.3 Hz, 1.5H), 1.21-1.23 (m, 3H), 1.19-1.21 (m,3H)

Other intermediates 7 were prepared by similar steps according to Scheme1 and either: (1) replacing (R)-2-methylpiperazine in Step E with analternately substituted or unsubstituted piperazine; and/or (2)replacing 3-methoxypropanoic acid in Step F with an alternate acid.

Example 2 Preparation of(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(17; wherein R^(1a) is hydrogen; R² is cyclopropyl; m is 1; R³ is3-methyl; and R⁸ is methoxyethyl) was prepared according to generalScheme 2, below.

Step L: 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (12)

To a solution of commercially available 1-cyclopropylethanone (11; 8.584g, 100 mmol) in 200 mL of anhydrous DMF was added1,1-dimethoxy-N,N-dimethylmethanamine (29.80 g, 250 mmol). The resultingmixture was stirred at 100° C. overnight. After removal of DMF andexcess of acetal, 13.9 g of title Compound was obtained as a crudeproduct and used in subsequent reaction without further purification. ¹HNMR (CHLOROFORM-d) δ 7.56 (d, J=12.8 Hz, 1H), 5.20 (d, J=12.5 Hz, 1H),2.78-3.08 (m, 6H), 1.79 (tt, J=7.9, 4.5 Hz, 1H), 0.94-1.04 (m, 2H),0.67-0.80 (m, 2H).

Step M: 6-cyclopropyl-2-hydroxynicotinonitrile (13)

3.532 g of 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one 12 and 2.032 gof cyanoacetamide in 10 mL of H₂O was treated with a premixed buffersolution of 0.33 mL of acetic acid, 0.82 mL of H₂O, and enough amount ofpiperidine to make solution basic. The resulting solution was refluxedfor 2 hrs and LC-MS showed the formation of desired product 13. Aftercooling to room temperature, the mixture was acidified with glacialacetic acid, and a brown yellowish precipitated was formed. The thickbrown slurry was filtered and filter cake was washed with H₂O andair-dried to give 1.30 g of title compound. MS (ES) M+H expected 161.1,found 161.0. ¹H NMR (CHLOROFORM-d) δ 13.60 (br. s., 1H), 7.77 (d, J=7.8Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 1.96-2.12 (m, 1H), 1.29-1.36 (m, 2H),1.04-1.11 (m, 2H).

Step N: 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (14)

To a solution of 6-cyclopropyl-2-hydroxynicotinonitrile (13; 0.32 g, 2.0mmol) in 5 mL of DCE was added NBS (0.534 g, 3.0 mmol) at roomtemperature. The reaction mixture was heated at reflux for 3 hours.After LC-MS showed completion of reaction, the reaction mixture wascooled to room temperature and poured into water. After extraction withmethylene chloride (3×5 mL), the combined organic layer was dried overanhy. Na₂SO₄ and concentrated in vacuo. Column chromatography (4%MeOH/DCM) afforded 0.45 g of 14. MS (ES) M+H expected 239.0, found238.9. ¹H NMR (CHLOROFORM-d) δ 8.49-8.72 (br. s., 1H), 7.93 (s, 1H),2.23-2.34 (m, 1H), 1.36-1.42 (m, 2H), 1.29-1.36 (m, 2H).

Step O: 5-bromo-3-cyano-6-cyclopropylpyridin-2-yltrifluoromethanesulfonate (15)

To a 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (14; 0.45 g, 1.882mmol) in 10 mL of methylene chloride was added DMAP (23.2 mg, 0.19mmol), and triethylamine (0.247 g, 2.45 mmol). The mixture was cooled to0° C. in an ice-water bath, and trifluoromethanesulfonic anhydride (0.69g, 2.45 mmol) was added dropwise via syringe. The resulting reactionmixture was stirred at 0° C. for 30 min before it was allowed to warm toroom temperature and stirred for additional 2 hours. After TLC showedthe complete conversion of starting material to product, the reactionmixture was concentrated and purified by column chromatography (20%ethyl acetate/petroleum ether) to afford 537 mg of 15. ¹H NMR(CHLOROFORM-d) δ 8.14-8.19 (m, 1H), 2.55-2.66 (m, 1H), 1.30 (dt, J=7.8,3.1 Hz, 2H), 1.21-1.27 (m, 2H).

Step P:(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (16)

A mixture of above triflate 15 (1.68 g, 4.6 mmol),(R)-2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9 mL,13.8 mmol) suspended in 5 mL of MeCN was subjected to microwave reactionat 175° C. for 60 min. After the mixture was concentrated under reducedpressure, the residue was extracted between ethyl acetate and water. Thecombined organic layer was then washed with aq. NaHCO₃, brine, driedover anhy. Na₂SO₄ and concentrated in vacuo to give 1.26 g of crude 16.MS (ES) M+H expected 321.1, found 321.2. ¹H NMR (CHLOROFORM-d) δ 7.78(s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H),2.96-3.00 (m, 2H), 2.71 (dd, J=12.9, 10.2 Hz, 1H), 2.42-2.52 (m, 1H),1.16 (d, J=6.3 Hz, 3H), 1.08 (s, 2H), 1.07 (d, J=3.8 Hz, 2H).

Step Q:(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(17)

To a 25 mL of round-bottom flask was added(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (16;1.26 g, 3.9 mmol), 3-methoxypropanoic acid (0.74 mL, 7.8 mmol), HATU(2.98 g, 7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL of methylenechloride. The resulting reaction mixture was stirred at room temperatureovernight until TLC showed the completion of the reaction. Reactionmixture was with Satd. NaHCO₃ and brine. The combined organic layer wasthen dried over anhy. Na₂SO₄ and concentrated in vacuo. Columnchromatography purification (30% EtOAc/petroleum ether) afforded 1.28 gof title compound as a white solid. MS (ES) M+H expected 407.1, found407.0. ¹H NMR (CHLOROFORM-d) δ 7.78-7.85 (m, 1H), 4.82-4.92 (m, 0.5H),4.50 (d, J=13.6 Hz, 0.5H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H),3.75-3.82 (m, 0.5H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 0.5H), 3.36 (s,3H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61(m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz,1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).

Other intermediates 17 were similarly prepared according to Scheme 2 byeither: (1) replacing (R)-2-methylpiperazine in Step P with analternately substituted or unsubstituted piperazine; and/or (2)replacing 3-methoxypropanoic acid in Step Q with an alternate acid.

Example 3 Preparation of(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(28; wherein R^(1a) is methyl; R² is cyclopropyl; m is 1; R³ is3-methyl; and R⁸ is methoxyethyl) was prepared according to generalScheme 3, below.

Step Aa: 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (24)

To a suspension of ammonium acetate (140 g, 1.82 mol) in 400 mL of EtOHwas added successively commercially available 1-cyclopropylethanone (22;22.5 mL, 22.7 mmol), acetaldehyde (21; 10 g, 22.7 mmol), and ethylcyanoacetate (23; 24.2 mL, 22.7 mmol). The resulting mixture was stirredat reflux temperature for 2 hrs and subsequently at room temperatureovernight. After the LC-MS showed the formation of the desired product,the solvent was removed under reduced pressure. Flash columnChromatography (10% MeOH/DCM) afforded 1.3 g of 24 as a white solid. MS(ES) M+H expected 175.1, found 175.1. ¹H NMR (DMSO-d6) δ 12.36 (br. s.,1H), 5.93 (s, 1H), 2.26 (s, 3H), 1.81-1.91 (m, 1H), 1.06-1.14 (m, 2H),0.91-0.95 (m, 2H).

Step Bb: 5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (25)

To a solution of 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (24;2.6 g, 15 mmol) in 10 mL of DCE was added NBS (4 g, 22.5 mmol) at roomtemperature. The reaction mixture was then heated at reflux for 3 hours.After LC-MS showed the completion of reaction, the mixture was cooled toroom temperature and poured into water and extracted with methylenechloride. The combined organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo. Column chromatography (4% MeOH/DCM) afforded 4 gof 25 as a brown solid. MS (ES) M+H expected 253.0, found 253.0. ¹H NMR(CHLOROFORM-d) δ 2.68 (s, 3H), 1.79-1.88 (m, 1H), 1.03-1.09 (m, 2H),0.93-1.01 (m, 2H).

Step Cc: 5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yltrifluoromethanesulfonate (26)

To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (25; 4.0g, 14.6 mmol) in 20 mL of methylene chloride was added DMAP (178 mg,1.46 mmol), and triethylamine (2.5 mL, 17.5 mmol). The mixture wascooled to 0° C. in an ice-water bath, and trifluoromethanesulfonicanhydride (3.7 mL, 21.9 mmol) was added dropwise by syringe. Theresulting reaction mixture was stirred at 0° C. for 30 min then allowedto warm to room temperature and stirred overnight. After TLC showed thecomplete conversion of starting material to product, the reactionmixture was concentrated and purified by column chromatography (20%EtOAc/petroleum ether) to afford 1.66 g of 26. ¹H NMR (CHLOROFORM-d) δ2.70 (s, 3H), 2.16-2.20 (m, 1H), 1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H).

Step Dd:(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(27)

A mixture of above triflate 26 (1.66 g, 4.3 mmol),(R)-2-methylpiperazine (738 mg, 6.46 mmol), and triethylamine (1.8 mL,12.9 mmol) suspended in 5 mL of MeCN was subjected to microwave reactionat 150° C. for 1 hour. After removal of solvent under reduced pressure,the residue was extracted between EtOAc and water. The organic layer wasthen washed with satd. aq. NaHCO₃ and brine, dried over anhy. Na₂SO₄ andconcentrated in vacuo. Flash column chromatography (10% DCM/MeOH)afforded 330 mg of 27 as a light yellowish solid. MS (ES) M+H expected335.1, found 335.2. ¹H NMR (CHLOROFORM-d) δ 4.08-4.16 (m, 0.5H),4.05-4.08 (m, 1H), 4.01-4.04 (m, 0.5H), 2.99-3.08 (m, 1H), 2.97 (d,J=8.8 Hz, 2H), 2.88-2.95 (m, 1H), 2.58-2.65 (m, 1H), 2.55-2.57 (m, 3H),1.77 (br. s., 1H), 1.12 (s, 1.5H), 1.10 (s, 1.5H), 1.05-1.09 (m, 2H),1.00-1.05 (m, 2H).

Step Ee:(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(28)

To a 50 mL of round-bottom flask was added(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(27; 1.12 g, 3.34 mmol), 3-methoxypropanoic acid (0.63 mL, 6.68 mmol),HATU (2.54 g, 6.68 mmol), DIPEA (3.8 g, 10 mmol) and 10 mL of methylenechloride. The resulting reaction mixture was stirred at room temperatureovernight until TLC showed the completion of the reaction. After washingthe reaction mixture with Satd. NaHCO₃, brine, the organic layer wasdried over anhy. Na₂SO₄ and concentrated in vacuo. Flash columnchromatography (20% EtOAc/petroleum ether) afforded 1.7 g of 28 as ayellowish solid. MS (ES) M+H expected 421.1, found 421.3. ¹H NMR(CHLOROFORM-d) δ 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.22(br. s., 0.5H), 3.95-4.13 (m, 2H), 3.78 (br. s., 0.5H), 3.74 (t, J=5.9Hz, 2H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H), 3.07-3.24 (m, 1.5H),2.90-3.06 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (s, 3H), 2.52-2.63 (m, 1H),2.17-2.21 (m, 1H), 1.37 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.3 Hz, 1.5H),1.09 (s, 2H), 1.05-1.08 (m, 2H).

Other intermediates 28 were similarly prepared according to Scheme 3 byeither: (1) replacing (R)-2-methylpiperazine in Step Dd with analternately substituted or unsubstituted piperazine; and/or (2)replacing 3-methoxypropanoic acid in Step Ee with an alternate acid.

Example 4 Preparation of(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)-nicotinonitrile(Compound 189)

A mixture of bromide 7 from Example 1 (26 mg, 0.06 mmol),4-(trifluoromethyl)phenylboronic acid (17 mg, 0.089 mmol), Pd(PPh₃)₄ (3mg, 0.003 mmol), and K₂CO₃ (16 mg, 0.119 mmol) suspended in 1 mL of DMFwas subjected to microwave reaction at 150° C. for 45 min. After thereaction, the reaction mixture was concentrated in vacuo, and theresidue was purified by column chromatography to afford 19 mg ofCompound 189 as yellowish oil. MS (ES) M+H expected 475.2, found 475.1.¹H NMR (CHLOROFORM-d) δ 7.70 (d, J=8.0 Hz, 2H), 7.60 (s, 1H), 7.38 (d,J=8.0 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=11.0 Hz, 0.5H), 4.44 (d,J=12.3 Hz, 1H), 4.32-4.39 (m, 1H), 4.28 (br. s., 0.5H), 3.83 (d, J=13.3Hz, 0.5H), 3.68-3.79 (m, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.36(br. s., 0.5H), 3.33 (br. s., 0.5H), 3.10-3.28 (m, 1.5H), 3.07 (dt,J=13.3, 1 Hz, 1H), 2.65-2.80 (m, 1H), 2.52-2.65 (m, 1H), 1.40 (d, J=6.5Hz, 1.5H), 1.30 (d, J=6.3 Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H).

Other Compounds of Formula II listed below, wherein R^(1b) is aryl orheteroaryl; and R² is isopropyl or cyclopropyl were similarly preparedusing any of intermediates 7 (Scheme 1), 17 (Scheme 2), or 28 (Scheme 3)as starting material.

(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(4-(trifluoromethyl)phenyl)nicotinonitrile(Compound 185)

¹H NMR (CHLOROFORM-d) δ 7.70 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.47-7.56(m, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.07 (d, J=3.5 Hz, 1H), 6.48-6.55 (m,1H), 4.86-4.96 (m, 1H), 4.43-4.59 (m, 2H), 4.38 (dt, J=13.3, 2.0 Hz,1H), 3.56 (br. s., 1H), 3.46 (dd, J=13.3, 3.8 Hz, 1H), 3.28 (td, J=12.4,3.4 Hz, 1H), 3.07 (quin, J=6.7 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.16(dd, J=6.7, 1.6 Hz, 6H). LC-MS: m/z 483.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(4-(trifluoromethyl)phenyl)nicotinonitrile(Compound 187)

¹H NMR (CHLOROFORM-d) δ 7.76 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (s,1H), 7.44-7.49 (m, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.56-6.63 (m, 1H), 4.75(br. s., 1H), 4.45 (d, J=13.1 Hz, 1H), 4.35-4.42 (m, 2H), 3.42-3.64 (m,1H), 3.31-3.41 (m, 1H), 3.18 (td, J=12.5, 3.5 Hz, 1H), 3.07 (dt, J=13.2,6.6 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.16 (dd, J=6.7, 1.9 Hz, 6H).LC-MS: m/z 483.2 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)nicotinonitrile(Compound 188)

¹H NMR (CHLOROFORM-d) δ 7.69 (d, J=8.3 Hz, 2H), 7.59 (s, 1H), 7.37 (d,J=8.0 Hz, 2H), 7.22 (dd, J=5.1, 1.1 Hz, 1H), 6.95-7.00 (m, 1H),6.89-6.95 (m, 1H), 4.95 (br. s., 0.5H), 4.59 (d, J=12.8 Hz, 0.5H),4.19-4.48 (m, 3H), 3.89-4.06 (m, 2H), 3.82 (d, J=13.6 Hz, 0.5H), 3.57(t, J=11.3 Hz, 0.5H), 3.20-3.38 (m, 1H), 3.08-3.20 (m, 1H), 3.00-3.08(m, 1H), 1.35 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.15 (d,J=6.5 Hz, 6H). LC-MS: m/z 513.1 (M+H)⁺.

(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-m-tolylnicotinonitrile(Compound 190)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.31 (t,J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.01-7.09 (m, 3H), 6.51 (dd,J=3.3, 1.8 Hz, 1H), 4.90 (br. s., 1H), 4.52 (d, J=13.3 Hz, 1H), 4.42 (d,J=13.8 Hz, 1H), 4.30-4.37 (m, 1H), 3.56 (br. s., 1H), 3.41 (dd, J=13.2,3.6 Hz, 1H), 3.24 (td, J=12.4, 3.3 Hz, 1H), 3.15 (dt, J=13.3, 6.7 Hz,1H), 2.40 (s, 3H), 1.48 (d, J=6.5 Hz, 3H), 1.15 (dd, J=6.8, 2.3 Hz, 6H).LC-MS: m/z 429.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-m-tolylnicotinonitrile(Compound 191)

¹H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.61 (s, 1H), 7.46 (t, J=1.6 Hz,1H), 7.31 (t, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.00-7.08 (m, 2H),6.59 (d, J=1.0 Hz, 1H), 4.74 (br. s., 1H), 4.20-4.50 (m, 3H), 3.41-3.61(m, 1H), 3.32 (dd, J=13.1, 3.0 Hz, 1H), 3.08-3.19 (m, 2H), 2.40 (s, 3H),1.45 (d, J=6.8 Hz, 3H), 1.08-1.19 (m, 6H). LC-MS: m/z 429.1 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-m-tolylnicotinonitrile(Compound 192)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.28-7.35 (m, 1H), 7.16-7.25 (m,2H), 7.00-7.07 (m, 2H), 6.89-6.99 (m, 2H), 4.94 (br. s., 0.5H), 4.58 (d,J=13.3 Hz, 0.5H), 4.33-4.43 (m, 1H), 4.19-4.33 (m, 2H), 3.90-4.05 (m,2H), 3.80 (d, J=13.3 Hz, 0.5H), 3.51-3.63 (m, 0.5H), 3.17-3.33 (m, 1H),3.10-3.17 (m, 1H), 2.99-3.10 (m, 1H), 2.40 (s, 3H), 1.36 (d, J=6.3 Hz,1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z459.1 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-m-tolylnicotinonitrile(Compound 193)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.19 (d,J=7.8 Hz, 1H), 7.01-7.08 (m, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=13.1Hz, 0.5H), 4.30-4.44 (m, 2H), 4.19-4.30 (m, 1H), 3.81 (d, J=13.6 Hz,0.5H), 3.71-3.78 (m, 2H), 3.52-3.65 (m, 0.5H), 3.38 (s, 3H), 3.24-3.36(m, 1H), 3.10-3.23 (m, 2H), 2.65-2.80 (m, 1H), 2.54-2.64 (m, 1H), 2.40(s, 3H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.15 (d,J=6.5 Hz, 6H). LC-MS: m/z 421.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-isopropylpiperazin-1-yl)-6-isopropyl-5-(4-(trifluoromethyl)phenyl)nicotinonitrile(Compound 195)

¹H NMR (CHLOROFORM-d) δ 7.67-7.84 (m, 3H), 7.57-7.64 (m, 1H), 7.45-7.53(m, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.58 (s, 1H), 4.84 (d, J=13.6 Hz, 1H),4.49-4.69 (m, 2H), 3.81-4.22 (m, 1H), 3.22-3.57 (br. s., 3H), 3.07 (dt,J=13.3, 6.7 Hz, 1H), 2.19-2.38 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.14 (d,J=6.8 Hz, 3H), 0.88-1.05 (m, 6H). LC-MS: m/z 511.1 (M+H)⁺.

(R)-6-isopropyl-2-(3-isopropyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)-nicotinonitrile(Compound 196)

¹H NMR (CHLOROFORM-d) δ 7.64-7.75 (m, 2H), 7.55-7.62 (m, 1H), 7.37-7.46(d, J=8.5 Hz, 2H), 7.22 (ddd, J=4.8, 3.2, 1.3 Hz, 1H), 6.87-7.02 (m,2H), 4.68-4.82 (m, 1.5H), 4.35-4.54 (m, 1.5H), 3.81-4.11 (m, 3H), 3.63(d, J=10.3 Hz, 0.5H), 3.37-3.53 (m, 0.5H), 3.08-3.20 (m, 1H), 2.96-3.08(m, 2H), 2.18-2.32 (m, 0.5H), 2.04-2.17 (m, 0.5H), 1.17 (dd, J=6.7, 3.6Hz, 3H), 1.13 (d, J=6.5 Hz, 3H), 1.08 (dd, J=11.0, 6.5 Hz, 3H),0.87-0.93 (m, 1.5H), 0.85 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 541.1 (M+H)⁺.

(R)-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)nicotinonitrile(Compound 197)

¹H NMR (CHLOROFORM-d) δ 7.66-7.76 (m, 2H), 7.59 (d, J=2.3 Hz, 1H), 7.38(d, J=8.0 Hz, 2H), 4.68-4.84 (m, 1.5H), 4.47-4.5 (s, 1.5H), 3.88 (d,J=13.6 Hz, 0.5H), 3.69-3.82 (m, 2H), 3.61 (d, J=10.3 Hz, 0.5H),3.42-3.52 (m, 0.5H), 3.38 (d, J=2.8 Hz, 3H), 3.12-3.27 (m, 2H),3.02-3.12 (m, 1H), 2.90-3.02 (m, 0.5H), 2.53-2.83 (m, 2H), 2.17-2.30 (m,0.5H), 1.98-2.16 (m, 0.5H), 1.18 (d, J=6.5 Hz, 3H), 1.14 (d, J=6.8 Hz,3H), 1.08 (dd, J=6.5, 2.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 1.5H), 0.85 (d,J=6.8 Hz, 1.5H). LC-MS: m/z 407.4 (M+H)⁺.

(R)-5-(4-fluorophenyl)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)nicotinonitrile(Compound 199)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.17-7.24(m, 2H), 7.08-7.16 (m, 2H), 6.38 (d, J=1.8 Hz, 1H), 4.68 (br. s., 1H),4.41 (d, J=13.1 Hz, 1H), 4.36 (d, J=13.1 Hz, 1H), 4.20-4.28 (d, J=13.6Hz, 1H), 3.39-3.59 (m, 1H), 3.25-3.37 (m, 1H), 3.03-3.18 (m, 2H), 2.41(s, 3H), 1.41 (d, J=6.5 Hz, 3H), 1.14 (dd, J=6.8, 2.3 Hz, 6H). LC-MS:m/z 447.2 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5-m-tolylnicotinonitrile(Compound 200)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.29 (d, J=2.0 Hz, 2H), 7.17-7.24(m, 1H), 7.08-7.16 (m, 2H), 6.38 (d, J=1.8 Hz, 1H), 4.68 (br. s., 1H),4.41 (d, J=13.1 Hz, 1H), 4.36 (d, J=13.1 Hz, 1H), 4.20-4.28 (d, J=13.6Hz, 1H), 3.39-3.59 (m, 4H), 3.25-3.37 (m, 4H), 3.03-3.18 (m, 8H), 2.41(s, 11H), 1.41 (d, J=6.5 Hz, 11H), 1.14 (dd, J=6.8, 2.3 Hz, 6H). LC-MS:m/z 443.3 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)-nicotinonitrile(Compound 201)

¹H NMR (CHLOROFORM-d) δ 7.70 (d, J=8.0 Hz, 2H), 7.57-7.64 (m, 1H), 7.37(d, J=8.0 Hz, 2H), 7.27-7.32 (m, 1H), 6.35-6.42 (m, 1H), 4.68 (br. s.,1H), 4.34-4.53 (m, 2H), 4.20-4.34 (m, 1H), 3.48 (d, J=4.8 Hz, 1H),3.28-3.40 (m, 1H), 3.16 (td, J=12.6, 3.4 Hz, 1H), 3.00-3.11 (m, 1H),2.41 (s, 3H), 1.38-1.48 (m, 3H), 1.16 (dd, J=6.8, 2.3 Hz, 6H). LC-MS:m/z 497.2 (M+H)⁺.

(R)-6-isopropyl-5-(4-isopropylphenyl)-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)nicotinonitrile(Compound 202)

¹H NMR (CHLOROFORM-d) δ 7.58-7.65 (m, 1H), 7.28 (d, J=8.3 Hz, 3H),7.11-7.20 (m, 2H), 6.37 (d, J=2.0 Hz, 1H), 4.59-4.68 (br. s., 1H),4.30-4.43 (m, 2H), 4.19 (br. s., 1H), 3.40-3.54 (m, 1H), 3.30 (dd,J=12.8, 3.0 Hz, 1H), 3.14-3.22 (m, 1H), 3.06-3.14 (m, 1H), 2.96 (spt,J=6.9 Hz, 1H), 2.41 (s, 3H), 1.39-1.45 (m, 3H), 1.30 (d, J=7.0 Hz, 6H),1.15 (dd, J=6.8, 3.0 Hz, 6H). LC-MS: m/z 471.3 (M+H)⁺.

(R)-5-(furan-3-yl)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)nicotinonitrile(Compound 203)

¹H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.49-7.53 (m, 1H), 7.43-7.47 (m,1H), 7.29 (d, J=1.8 Hz, 1H), 6.45 (d, J=0.8 Hz, 1H), 6.36 (d, J=1.8 Hz,1H), 4.68 (br. s., 1H), 4.39 (d, J=13.1 Hz, 1H), 4.34 (d, J=13.1 Hz,1H), 4.18-4.26 (br. s., 1H), 3.38-3.56 (m, 1H), 3.22-3.35 (m, 2H), 3.11(td, J=12.6, 3.4 Hz, 1H), 2.36-2.47 (m, 3H), 1.39 (d, J=6.5 Hz, 3H),1.18 (dd, J=6.7, 1.6 Hz, 6H). LC-MS: m/z 419.2 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-5-(furan-3-yl)-6-isopropylnicotinonitrile(Compound 204)

¹H NMR (CHLOROFORM-d) δ 7.72-7.77 (m, 1H), 7.64 (s, 1H), 7.50 (t, J=1.8Hz, 1H), 7.44-7.47 (m, 2H), 6.58 (dd, J=1.8, 0.8 Hz, 1H), 6.45 (dd,J=1.8, 0.8 Hz, 1H), 5.30 (s, 1H), 4.73 (br. s., 1H), 4.38 (s, 1H), 4.41(s, 1H), 4.31 (t, J=2.1 Hz, 1H), 4.35 (t, J=2.0 Hz, 1H), 3.48 (br. s.,1H), 3.32 (dd, J=9.9, 3.1 Hz, 1H), 3.24-3.30 (m, 1H), 3.14 (td, J=12.5,3.5 Hz, 1H), 1.42 (d, J=7.0 Hz, 3H), 1.19 (dd, J=6.8, 1.0 Hz, 6H).LC-MS: m/z 405.2 (M+H)⁺.

(R)-5-(furan-3-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 205)

¹H NMR (CHLOROFORM-d) δ 7.63 (s, 1H), 7.50 (t, J=1.8 Hz, 1H), 7.42-7.47(m, 1H), 6.44 (dd, J=1.8, 0.8 Hz, 1H), 4.92 (br. s., 0.5H), 4.54 (d,J=13.1 Hz, 0.5H), 4.38 (dd, J=12.2, 2.1 Hz, 1H), 4.17-4.35 (m, 2H), 3.80(d, J=13.1 Hz, 0.5H), 3.74 (t, J=6.5 Hz, 2H), 3.51-3.62 (m, 0.5H),3.36-3.39 (m, 3H), 3.23-3.35 (m, 2H), 3.06-3.17 (m, 1H), 2.64-2.80 (m,1H), 2.51-2.63 (m, 1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.0 Hz,1.5H), 1.19 (d, J=6.8 Hz, 6H). LC-MS: m/z 397.2 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(4-isopropylphenyl)nicotinonitrile(Compound 206)

¹H NMR (CHLOROFORM-d) δ 7.72-7.77 (m, 1H), 7.61 (s, 1H), 7.46 (t, J=1.6Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12-7.19 (m, 2H), 6.59 (dd, J=1.8, 0.8Hz, 1H), 4.74 (br. s., 1H), 4.39 (d, J=13.3 Hz, 1H), 4.33 (dt, J=13.2,1.9 Hz, 2H), 3.49 (br. s., 1H), 3.32 (dd, J=13.2, 3.4 Hz, 1H), 3.08-3.23(m, 2H), 2.96 (dt, J=13.8, 6.9 Hz, 1H), 1.45 (d, J=6.8 Hz, 3H), 1.30 (d,J=7.0 Hz, 6H), 1.15 (dd, J=6.5, 2.3 Hz, 6H). LC-MS: m/z 457.2 (M+H)⁺.

(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 207)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.17-7.24 (m, 2H), 7.08-7.16 (m,2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.0 Hz, 0.5H), 4.40 (dd, J=12.2,1.9 Hz, 1H), 4.19-4.35 (m, 2H), 3.82 (d, J=12.5 Hz, 0.5H), 3.69-3.78 (m,2H), 3.53-3.63 (m, 0.5H), 3.38 (s, 3H), 3.26-3.35 (m, 1H), 3.13-3.22 (m,1H), 3.03-3.12 (m, 1H), 2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 1.40 (d,J=6.3 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H).LC-MS: m/z 425.2 (M+H)⁺.

(R)-6-isopropyl-5-(4-isopropylphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 208)

¹H NMR (CHLOROFORM-d) δ 7.59-7.65 (m, 1H), 7.29-7.33 (m, 2H), 7.14-7.22(m, 2H), 4.95 (br. s., 0.5H), 4.58 (d, J=13.1 Hz, 0.5H), 4.37-4.44 (m,1H), 4.22-4.37 (m, 2H), 3.83 (d, J=13.3 Hz, 0.5H), 3.70-3.80 (m, 2H),3.55-3.67 (m, 0.5H), 3.40 (s, 3H), 3.33 (t, J=12.3 Hz, 1H), 3.15-3.25(m, 2H), 2.98 (quin, J=6.9 Hz, 1H), 2.67-2.83 (m, 1H), 2.55-2.67 (m,1H), 1.43 (d, J=5.8 Hz, 1.5H), 1.34 (m, 1.5H), 1.32 (d, J=7.0 Hz, 6H),1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 449.2 (M+H)⁺.

(R)-5-(benzofuran-2-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 209)

¹H NMR (CHLOROFORM-d) δ 8.12 (s, 1H), 7.61 (dd, J=7.7, 0.9 Hz, 1H),7.48-7.56 (m, 1H), 7.32 (td, J=7.7, 1.5 Hz, 1H), 7.24-7.29 (m, 1H),6.78-6.88 (m, 1H), 4.93 (br. s., 0.5H), 4.38-4.64 (m, 2H), 4.27 (br. s.,0.5H), 3.83 (d, J=12.8 Hz, 1H), 3.75 (br. s., 2H), 3.55 (quin, J=6.7 Hz,2H), 3.38 (s, 3H), 3.08-3.29 (m, 2H), 2.66-2.83 (m, 1H), 2.60 (br. s.,1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.33 (br. s., 1.5H), 1.28 (d, J=6.5 Hz,6H). LC-MS: m/z 447.1 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyrimidin-5-yl)nicotinonitrile(Compound 210)

¹H NMR (CHLOROFORM-d) δ 9.23-9.28 (m, 1H), 8.69 (s, 2H), 7.62 (s, 1H),4.94 (br. s., 0.5H), 4.56 (d, J=9.5 Hz, 0.5H), 4.37-4.53 (m, 2H), 4.29(br. s., 0.5H), 3.84 (d, J=13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.52-3.64(m, 0.5H), 3.40-3.46 (m, 0.5H), 3.38 (s, 3H), 3.20-3.32 (m, 1H), 3.16(d, J=9.5 Hz, 1H), 2.93-3.04 (m, 1H), 2.65-2.78 (m, 1H), 2.52-2.64 (m,1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 1.19 (dd,J=6.7, 1.1 Hz, 6H). LC-MS: m/z 409.2 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(naphthalen-2-yl)nicotinonitrile(Compound 211)

¹H NMR (CHLOROFORM-d) δ 7.83-7.97 (m, 3H), 7.66-7.77 (m, 2H), 7.49-7.60(m, 2H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d,J=12.8 Hz, 0.5H), 4.42 (d, J=12.8 Hz, 1H), 4.30-4.38 (m, 1H), 4.27 (br.s., 1H), 3.83 (d, J=13.3 Hz, 0.5H), 3.69-3.79 (m, 2H), 3.54-3.65 (m,0.5H), 3.39 (s, 3H), 3.29-3.38 (m, 1H), 3.18-3.24 (m, 1H), 3.06-3.17 (m,1H), 2.66-2.83 (m, 1H), 2.52-2.65 (m, 1H), 1.42 (d, J=7.3 Hz, 1.5H),1.32 (d, J=6.5 Hz, 1.5H), 1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 457.1(M+H)⁺.

(R)-6-isopropyl-5-(3-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 212)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.34 (t, J=7.9 Hz, 1H), 6.92 (dd,J=8.3, 1.8 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.74-6.79 (m, 1H), 4.93 (br.s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.39 (d, J=13.6 Hz, 1H), 4.21-4.34(m, 2H), 3.84 (s, 3H), 3.79 (d, J=8.0 Hz, 0.5H), 3.70-3.77 (m, 2H),3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.26-3.36 (m, 1H), 3.12-3.22 (m, 2H),2.65-2.80 (m, 1H), 2.52-2.64 (m, 1H), 1.41 (d, J=1.5 Hz, 4H), 1.31 (d,J=6.5 Hz, 1.5H), 1.10-1.19 (m, 6H). LC-MS: m/z 437.1 (M+H)⁺.

(R)-2-isopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4′-bipyridine-5-carbonitrile(Compound 213)

¹H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.3 Hz, 2H), 7.61 (s, 1H), 7.22 (d,J=5.5 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=9.8 Hz, 0.5H), 4.34-4.51(m, 2H), 4.28 (br. s., 1H), 3.83 (d, J=13.3 Hz, 0.5H), 3.68-3.79 (m,2H), 3.58 (t, J=11.0 Hz, 0.5H), 3.38 (s, 3H), 3.14-3.28 (m, 2H),3.03-3.14 (m, 1H), 2.65-2.83 (m, 1H), 2.52-2.65 (m, 1H), 1.39 (d, J=6.3Hz, 1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z408.1 (M+H)⁺.

(R)-6-isopropyl-5-(4-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 214)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.11-7.20 (m, 2H), 6.92-7.01 (m,2H), 4.92 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.37 (d, J=12.5 Hz,1H), 4.29 (d, J=13.1 Hz, 2H), 3.86 (s, 3H), 3.81 (d, J=13.6 Hz, 0.5H),3.75 (br. s., 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=13.2Hz, 1H), 3.11-3.20 (m, 2H), 2.66-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.41(d, J=6.0 Hz, 1.5H), 1.31 (d, J=5.8 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H).LC-MS: m/z 437.3 (M+H)⁺.

(R)-5-(4-chlorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 215)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.38-7.43 (m, 2H), 7.14-7.20 (m,2H), 4.93 (br. s., 0.5H), 4.55 (d, J=12.5 Hz, 0.5H), 4.40 (d, J=12.8 Hz,1H), 4.21-4.36 (m, 2H), 3.82 (d, J=13.6 Hz, 0.5H), 3.69-3.78 (m, 2H),3.53-3.63 (m, 0.5H), 3.38 (s, 3H), 3.27-3.37 (m, 1H), 3.11-3.23 (m, 1H),3.02-3.11 (m, 1H), 2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 1.40 (d, J=6.5Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.5 Hz, 6H). LC-MS: m/z441.1 (M+H)⁺.

5-(4-ethylphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 216)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.15(d, J=8.0 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=12.5 Hz, 0.5H), 4.38(d, J=12.3 Hz, 1H), 4.30 (d, J=12.3 Hz, 2H), 3.81 (d, J=13.3 Hz, 0.5H),3.75 (br. s., 2H), 3.51-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=13.6Hz, 1H), 3.12-3.22 (m, 2H), 3.10 (d, J=14.3 Hz, 0.5H), 2.77 (br. s.,0.5H), 2.71 (q, J=7.5 Hz, 2H), 2.61 (br. s., 1H), 1.41 (d, J=6.0 Hz,1.5H), 1.32 (br. s., 1.5H), 1.29 (t, J=7.5 Hz, 3H), 1.15 (d, J=6.8 Hz,6H). LC-MS: m/z 435.3 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(naphthalen-1-yl)nicotinonitrile(Compound 217)

¹H NMR (CHLOROFORM-d) δ 7.92 (t, J=7.4 Hz, 2H), 7.63 (s, 1H), 7.49-7.57(m, 2H), 7.39-7.47 (m, 2H), 7.27-7.34 (m, 1H), 4.96 (br. s., 0.5H), 4.59(d, J=12.5 Hz, 0.5H), 4.45 (d, J=13.3 Hz, 1H), 4.32-4.41 (m, 1H), 4.30(br. s., 1H), 3.85 (d, J=13.6 Hz, 0.5H), 3.70-3.81 (m, 2H), 3.55-3.67(m, 0.5H), 3.39 (s, 3H), 3.07-3.27 (m, 2H), 2.67-2.76 (m, 2H), 2.53-2.66(m, 1H), 1.45 (d, J=5.5 Hz, 1.5H), 1.36 (d, J=6.5 Hz, 1.5H), 1.06 (d,J=6.5 Hz, 6H). LC-MS: m/z 457.3 (M+H)⁺.

(R)-5-(3-chlorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 218)

¹H NMR (CHLOROFORM-d) δ 7.56-7.61 (m, 1H), 7.35-7.39 (m, 2H), 7.21-7.25(m, 1H), 7.11-7.14 (m, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz,0.5H), 4.42 (d, J=12.5 Hz, 1H), 4.29-4.37 (m, 1H), 4.26 (br. s., 1H),3.82 (d, J=13.6 Hz, 0.5H), 3.68-3.78 (m, 2H), 3.53-3.65 (m, 0.5H), 3.38(s, 3H), 3.28-3.37 (m, 1H), 3.12-3.24 (m, 1H), 3.04-3.12 (m, 1H),2.65-2.80 (m, 1H), 2.50-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d,J=6.5 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 441.2 (M+H)⁺.

(R)-5-(3,4-dimethylphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 220)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.00 (s,1H), 6.97 (dd, J=7.7, 1.6 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=13.1Hz, 0.5H), 4.32-4.42 (m, 1H), 4.29 (d, J=12.8 Hz, 1H), 3.78-3.85 (m,0.5H), 3.71-3.77 (m, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.24-3.35(m, 1H), 3.17 (dt, J=13.3, 6.7 Hz, 2H), 3.01-3.12 (m, 1H), 2.65-2.80 (m,1H), 2.53-2.63 (m, 1H), 2.31 (d, J=3.0 Hz, 6H), 1.40 (d, J=6.5 Hz,1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.5 Hz, 6H). LC-MS: m/z435.4 (M+H)⁺.

(R)-5-(3-fluoro-4-methylphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 221)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.90-6.95(m, 1H), 6.89 (dd, J=5.8, 1.3 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d,J=12.8 Hz, 0.5H), 4.21-4.45 (m, 3H), 3.81 (d, J=13.3 Hz, 0.5H),3.70-3.77 (m, 2H), 3.52-3.63 (m, 0.5H), 3.38 (s, 3H), 3.26-3.37 (m, 1H),3.10-3.18 (m, 2H), 2.65-2.80 (m, 1H), 2.53-2.63 (m, 1H), 2.33 (d, J=1.5Hz, 3H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d,J=6.8 Hz, 6H). LC-MS: m/z 439.4 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-phenylnicotinonitrile(Compound 222)

¹H NMR (CHLOROFORM-d) δ 7.56-7.61 (m, 1H), 7.35-7.39 (m, 3H), 7.21-7.25(m, 2H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.42 (d, J=12.5Hz, 1H), 4.29-4.37 (m, 1H), 4.26 (br. s., 1H), 3.82 (d, J=13.6 Hz,0.5H), 3.68-3.78 (m, 2H), 3.53-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.37(m, 1H), 3.12-3.24 (m, 1H), 3.04-3.12 (m, 1H), 2.65-2.80 (m, 1H),2.50-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H),1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 407.4 (M+H)⁺.

(R)-5-(3,4-dimethoxyphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 223)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.78 (dd,J=8.2, 1.9 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 4.88-4.96 (m, 0.5H), 4.55(d, J=13.1 Hz, 0.5H), 4.18-4.46 (m, 3H), 3.93 (s, 3H), 3.89 (s, 3H),3.78-3.86 (m, 0.5H), 3.71-3.78 (m, 2H), 3.52-3.64 (m, 0.5H), 3.38 (s,3H), 3.31 (t, J=10.8 Hz, 1H), 3.10-3.22 (m, 2H), 2.65-2.80 (m, 1H),2.52-2.64 (m, 1H), 1.33 (s, 1.5H), 1.28 (s, 1.5H), 1.16 (d, J=6.8 Hz,6H). LC-MS: m/z 467.3 (M+H)⁺.

(R)-5-(benzo[d][1,3]-dioxol-5-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 224)

¹H NMR (CHLOROFORM-d) δ 7.57 (s, 1H), 6.83-6.90 (m, 1H), 6.64-6.73 (m,2H), 6.02 (s, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.5 Hz, 0.5H),4.20-4.43 (m, 3H), 3.81 (d, J=12.8 Hz, 0.5H), 3.74 (t, J=6.3 Hz, 2H),3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.25-3.36 (m, 1H), 3.10-3.22 (m, 2H),2.64-2.80 (m, 1H), 2.52-2.64 (m, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d,J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 451.3 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(trifluoromethoxy)phenyl)nicotinonitrile(Compound 230)

¹H NMR (CHLOROFORM-d) δ 7.58-7.63 (m, 1H), 7.42-7.51 (m, 1H), 7.22-7.26(m, 1H), 7.18 (dd, J=7.8, 1.3 Hz, 1H), 7.11 (s, 1H), 4.93 (br. s.,0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.27-4.46 (m, 3H), 3.78-3.88 (m,0.5H), 3.75 (t, J=6.4 Hz, 2H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H),3.29-3.36 (m, 1H), 3.13-3.24 (m, 1H), 3.07 (dt, J=13.3, 6.7 Hz, 1H),2.65-2.81 (m, 1H), 2.52-2.64 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d,J=6.3 Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 491.3 (M+H)⁺.

(R)-5-(3-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 231)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.39 (td, J=8.0, 6.1 Hz, 1H),7.05-7.13 (m, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.95 (dt, J=9.4, 2.1 Hz, 1H),4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.26-4.45 (m, 3H), 3.82(d, J=13.1 Hz, 0.5H), 3.75 (t, J=6.1 Hz, 2H), 3.51-3.64 (m, 0.5H), 3.38(s, 3H), 3.27-3.35 (m, 1H), 3.16-3.23 (m, 1H), 3.09-3.14 (m, 1H),2.65-2.81 (m, 1H), 2.60 (t, J=5.9 Hz, 1H), 1.40 (d, J=6.3 Hz, 1.5H),1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 443.3(M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(trifluoromethoxy)phenyl)nicotinonitrile(Compound 232)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.27 (s, 4H), 4.93 (br. s., 0.5H),4.49-4.61 (m, 9.5H), 4.26-4.47 (m, 3H), 3.82 (d, J=13.6 Hz, 0.5H),3.72-3.77 (m, 2H), 3.51-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.36 (m, 1H),3.13-3.23 (m, 1H), 3.08 (dt, J=13.3, 6.7 Hz, 1H), 2.65-2.80 (m, 1H),2.60 (t, J=5.9 Hz, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz,1.5H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 491.3 (M+H)⁺.

(R)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 233)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.27 (s, 4H), 4.93 (br. s., 0.5H),4.49-4.61 (m, 0.5H), 4.26-4.47 (m, 3H), 3.82 (d, J=13.6 Hz, 0.5H),3.72-3.77 (m, 2H), 3.51-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.36 (m, 1H),3.13-3.23 (m, 1H), 3.08 (dt, J=13.3, 6.7 Hz, 1H), 2.65-2.80 (m, 1H),2.60 (t, J=5.9 Hz, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz,1.5H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 465.3 (M+H)⁺.

(R)-6-isopropyl-5-(isoquinolin-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 234)

¹H NMR (CHLOROFORM-d) δ 9.33 (s, 1H), 8.37 (s, 1H), 8.06-8.16 (m, 1H),7.64-7.69 (m, 2H), 7.45-7.50 (m, 2H), 4.96 (br. s., 0.5H), 4.58 (br. s.,0.5H), 4.31-4.54 (m, 3H), 3.86 (d, J=12.5 Hz, 0.5H), 3.76 (t, J=6.4 Hz,2H), 3.56-3.67 (m, 0.5H), 3.42 (d, J=3.8 Hz, 1H), 3.36-3.40 (m, 3H),3.08-3.33 (m, 1H), 2.65-2.78 (m, 2H), 2.54-2.64 (m, 1H), 1.44 (d, J=4.5Hz, 1.5H), 1.35 (d, J=6.0 Hz, 1.5H), 1.05-1.11 (m, 6H). LC-MS: m/z 458.2(M+H)⁺.

(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 219)

¹H NMR (CHLOROFORM-d) δ 7.57 (s, 1H), 7.31-7.39 (m, 2H), 7.27 (s, 1H),7.10-7.18 (m, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H),4.07-4.33 (m, 3H), 3.77-3.84 (m, 0.5H), 3.71-3.76 (m, 2H), 3.48-3.60 (m,0.5H), 3.36-3.41 (m, 3H), 3.25 (t, J=10.4 Hz, 1H), 3.06-3.18 (m, 1H),2.63-2.79 (m, 1H), 2.51-2.62 (m, 1H), 1.95-2.07 (m, 1H), 1.38 (d, J=6.5Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.12-1.18 (m, 2H), 0.91-0.97 (m,2H). LC-MS: m/z 423.3 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-m-tolylnicotinonitrile(Compound 225)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.30-7.36 (m, 1H), 7.14-7.22 (m,3H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 3.80-4.36 (m, 3H),3.80 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37(s, 3H), 3.19-3.29 (m, 1H), 3.07-3.17 (m, 1H), 2.63-2.80 (m, 1H),2.53-2.62 (m, 1H), 2.41 (s, 3H), 2.03-2.13 (m, 1H), 1.39 (d, J=5.8 Hz,1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 1.11-1.17 (m, 2H), 0.89-0.97 (m, 2H).LC-MS: m/z 419.3 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)nicotinonitrile(Compound 226)

¹H NMR (CHLOROFORM-d) δ 7.71 (d, J=8.0 Hz, 2H), 7.60 (s, 1H), 7.52 (d,J=8.0 Hz, 2H), 4.82-4.95 (m, 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.17-4.39(m, 3H), 3.80 (d, J=13.6 Hz, 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.49-3.62(m, 0.5H), 3.37 (s, 3H), 3.24-3.33 (m, 1H), 3.03-3.15 (m, 1H), 2.63-2.80(m, 1H), 2.51-2.62 (m, 1H), 1.93-2.02 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H),1.28 (d, J=3.5 Hz, 1.5H), 1.14-1.20 (m, 2H), 0.93-0.99 (m, 2H). LC-MS:m/z 473.3 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(trifluoromethoxy)phenyl)nicotinonitrile(Compound 227)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.41-7.44 (m, 1H), 7.38-7.41 (m,1H), 7.30 (s, 1H), 7.28 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=11.5Hz, 0.5H), 4.12-4.34 (m, 3H), 3.81 (br. s., 0.5H), 3.74 (t, J=6.3 Hz,2H), 3.55 (t, J=11.4 Hz, 0.5H), 3.37 (s, 3H), 3.26 (br. s., 1H), 3.11(br. s., 1H), 2.63-2.78 (m, 1H), 2.58 (d, J=5.8 Hz, 1H), 1.95-2.05 (m,1H), 1.38 (d, J=5.8 Hz, 1.5H), 1.28 (d, J=5.8 Hz, 1.5H), 1.13-1.18 (m,2H), 0.93-0.99 (m, 2H). LC-MS: m/z 489.2 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(trifluoromethoxy)phenyl)-nicotinonitrile(Compound 228)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.33 (d,J=7.8 Hz, 1H), 7.27 (br. s., 1H), 7.21-7.26 (m, 1H), 4.90 (br. s.,0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.17-4.36 (m, 3H), 3.77-3.86 (m,0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.51-3.62 (m, 0.5H), 3.37 (s, 3H), 3.28(t, J=8.9 Hz, 1H), 3.12 (d, J=10.8 Hz, 1H), 2.64-2.80 (m, 1H), 2.52-2.63(m, 1H), 1.96-2.04 (m, 1H), 1.35-1.42 (m, 1.5H), 1.28 (d, J=5.5 Hz,1.5H), 1.14-1.20 (m, 2H), 0.93-1.01 (m, 2H). LC-MS: m/z 489.2 (M+H)⁺.

(R)-6-cyclopropyl-5-(3-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 229)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.41 (td, J=7.8, 6.1 Hz, 1H),7.14-7.19 (m, 1H), 7.04-7.13 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d,J=13.1 Hz, 0.5H), 4.12-4.34 (m, 3H), 3.77-3.85 (m, 0.5H), 3.74 (t, J=6.1Hz, 2H), 3.48-3.61 (m, 0.5H), 3.37 (s, 3H), 3.26 (t, J=9.4 Hz, 1H),3.06-3.16 (m, 1H), 2.64-2.79 (m, 1H), 2.51-2.62 (m, 1H), 1.99-2.08 (m,1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.12-1.19 (m,2H), 0.93-0.99 (m, 2H). LC-MS: m/z 423.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(3-fluoro-4-methylphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 235)

¹H NMR (CHLOROFORM-d) δ 7.57 (s, 1H), 7.21-7.26 (m, 1H), 7.06 (s, 1H),7.01-7.05 (m, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=12.8 Hz, 0.5H),4.11-4.33 (m, 3H), 3.80 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H),3.49-3.60 (m, 0.5H), 3.36-3.41 (m, 3H), 3.25 (t, J=9.8 Hz, 1H),3.03-3.15 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.61 (m, 1H), 2.32 (d, J=1.5Hz, 3H), 2.01-2.09 (m, 1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.26-1.30 (m,1.5H), 1.12-1.17 (m, 2H), 0.92-0.97 (m, 2H). LC-MS: m/z 437.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(3-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 236)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.32-7.38 (m, 1H), 6.94-6.99 (m,1H), 6.87-6.94 (m, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H),4.18-4.26 (m, J=12.7 Hz, 3H), 3.84 (s, 3H), 3.81 (d, J=5.5 Hz, 0.5H),3.74 (t, J=6.1 Hz, 2H), 3.55 (t, J=11.0 Hz, 0.5H), 3.37 (s, 3H), 3.25(t, J=10.2 Hz, 1H), 3.03-3.15 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.62 (m,1H), 2.05-2.15 (m, 1H), 1.39 (d, J=6.0 Hz, 1.5H), 1.29 (d, J=6.3 Hz,1.5H), 1.11-1.18 (m, 2H), 0.91-0.96 (m, 2H). LC-MS: m/z 435.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(3,4-dimethoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 237)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 6.92-6.95 (m, 2H), 6.88 (s, 1H),4.89 (br. s., 0.5H), 4.53 (d, J=14.1 Hz, 0.5H), 4.16-4.30 (m, 3H), 3.93(s, 3H), 3.90 (s, 3H), 3.78-3.84 (m, 0.5H), 3.71-3.77 (m, 2H), 3.55 (br.s., 0.5H), 3.37 (s, 1H), 3.24 (br. s., 1H), 3.03-3.09 (m., 1H),2.66-2.79 (m, 1H), 2.59 (br. s., 1H), 2.08-2.15 (m, 1.5H), 1.38 (br. s.,1.5H), 1.13-1.17 (m, 2H), 0.93 (dd, J=8.0, 3.3 Hz, 2H). LC-MS: m/z 465.1(M+H)⁺.

(R)-6-cyclopropyl-5-(isoquinolin-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 242)

¹H NMR (DMSO-d₆) δ 7.47 (dd, J=5.0, 3.0 Hz, 1H), 7.17 (dd, J=2.8, 1.3Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H), 4.91 (br. s., 0.5H), 4.55 (d,J=10.8 Hz, 0.5H), 3.98-4.27 (m, 3H), 3.75 (q, J=6.0 Hz, 2.5H), 3.53-3.63(m, 0.5H), 3.40 (s, 3H), 3.11-3.25 (m, 1H), 2.94-3.06 (m, 1H), 2.69-2.81(m, 1H), 2.67 (d, J=7.3 Hz, 1H), 2.25 (s, 3H), 1.71-1.78 (m, 1H), 1.42(d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.06-1.08 (m, 2H),0.83-0.88 (m, 2H). LC-MS: m/z 456.2 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(thiophen-3-yl)nicotinonitrile(Compound 246)

¹H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.41 (dd, J=4.8, 3.0 Hz, 1H), 7.29(dd, J=3.0, 1.3 Hz, 1H), 7.18 (dd, J=5.0, 1.3 Hz, 1H), 4.90 (br. s.,0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.14-4.32 (m, 2.5H), 3.67-3.84 (m,2.5H), 3.55 (br. s., 0.5H), 3.18-3.34 (m, 1H), 2.96-3.18 (m, 1.5H),2.50-2.71 (m, 2H), 2.12-2.23 (m, 1H), 1.34-1.41 (m, 1.5H), 1.24-1.30 (m,1.5H), 1.12-1.18 (m, 2H), 0.92-1.02 (m, 2H). LC-MS: m/z 411.3 (M+H)⁺.

(R)-5-(benzo[b]thiophen-2-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 247)

¹H NMR (CHLOROFORM-d) δ 7.82-7.87 (m, 1H), 7.78-7.82 (m, 1H), 7.77 (s,1H), 7.33-7.42 (m, 2H), 7.32 (s, 1H), 4.90 (br. s., 0.5H), 4.52 (d,J=12.8 Hz, 0.5H), 4.24-4.39 (m, 3H), 3.70-3.80 (m, 2.5H), 3.35-3.41 (m,3H), 3.29 (t, J=9.8 Hz, 1H), 3.03-3.20 (m, 1.5H), 2.63-2.78 (m, 1H),2.52-2.63 (m, 1H), 2.34-2.44 (m, 1H), 1.37 (d, J=6.0 Hz, 1.5H),1.23-1.29 (m, 1.5H), 1.15-1.21 (m, 2H), 0.95-1.06 (m, 2H). LC-MS: m/z461.3 (M+H)⁺.

(R)-5-(3-chloro-4-fluorophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 248)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.45 (dd, J=6.9, 1.9 Hz, 1H),7.22-7.28 (m, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=12.8 Hz, 0.5H),4.16-4.37 (m, 3H), 3.70-3.81 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.37-3.42(m, 3H), 3.28 (t, J=10.2 Hz, 1H), 3.12 (d, J=11.0 Hz, 1H), 2.65-2.87 (m,1H), 2.55-2.65 (m, 1H), 1.94-2.05 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H),1.28 (d, J=4.0 Hz, 1.5H), 1.14-1.21 (m, 2H), 0.94-1.03 (m, 2H). LC-MS:m/z 457.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(2-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 249)

¹H NMR (CHLOROFORM-d) δ 7.62 (s, 1H), 7.37-7.45 (m, 1H), 7.30-7.36 (m,1H), 7.22-7.27 (m, 1H), 7.19 (t, J=9.0 Hz, 1H), 4.92 (br. s., 0.5H),4.54 (d, J=13.3 Hz, 0.5H), 4.19-4.37 (m, 3H), 3.78-3.86 (m, 0.5H),3.70-3.78 (m, 2H), 3.51-3.61 (m, 0.5H), 3.39 (s, 3H), 3.27 (t, J=12.5Hz, 1H), 3.02-3.16 (m, 1H), 2.65-2.82 (m, 1H), 2.54-2.64 (m, 1H),1.83-1.90 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H),1.12-1.19 (m, 2H), 0.92-0.98 (m, 2H). LC-MS: m/z 423.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(2,4-difluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 250)

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.26-7.35 (m, 1H), 6.91-7.04 (m,2H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.18-4.37 (m, 3H),3.78-3.85 (m, 0.5H), 3.71-3.78 (m, 2H), 3.51-3.62 (m, 0.5H), 3.39 (s,3H), 3.23-3.33 (m, 1H), 3.14 (d, J=10.5 Hz, 1H), 2.65-2.80 (m, 1H),2.53-2.63 (m, 1H), 1.77-1.85 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d,J=6.5 Hz, 1.5H), 1.11-1.19 (m, 2H), 0.96 (dd, J=7.8, 3.0 Hz, 2H). LC-MS:m/z 441.3 (M+H)⁺.

(R)-2-cyclopropyl-6-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,3′-bipyridine-5-carbonitrile(Compound 252)

¹H NMR (CHLOROFORM-d) δ 8.18 (d, J=2.3 Hz, 1H), 7.60 (dd, J=8.5, 2.5 Hz,1H), 7.56 (s, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d,J=13.1 Hz, 0.5H), 4.15-4.36 (m, 3H), 3.96-4.02 (m, 3H), 3.76-3.86 (m,0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.53-3.61 (m, 0.5H), 3.37 (s, 3H),3.21-3.31 (m, 1H), 3.12 (d, J=11.3 Hz, 1H), 2.63-2.80 (m, 1H), 2.51-2.62(m, 1H), 1.93-2.04 (m, 1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.28 (d, J=6.3 Hz,1.5H), 1.12-1.19 (m, 2H), 0.92-1.00 (m, 2H). LC-MS: m/z 436.2 (M+H)⁺.

(R)-6-cyclopropyl-5-(1H-indol-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 253)

¹H NMR (CHLOROFORM-d) δ 8.28 (br. s., 1H), 7.66 (s, 1H), 7.63 (s, 1H),7.46 (d, J=8.3 Hz, 1H), 7.29 (t, J=2.8 Hz, 1H), 7.20 (dd, J=8.3, 1.8 Hz,1H), 6.60 (t, J=2.1 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz,0.5H), 4.12-4.33 (m, 3H), 3.81 (br. s., 0.5H), 3.75 (t, J=6.4 Hz, 2H),3.51-3.63 (m, 0.5H), 3.38 (s, 3H), 3.22 (d, J=14.1 Hz, 1H), 3.01-3.17(m, 1H), 2.66-2.81 (m, 1H), 2.62 (t, J=5.8 Hz, 1H), 2.11-2.21 (m, 1H),1.41 (d, J=5.5 Hz, 1.5H), 1.31 (d, J=6.3 Hz, 1.5H), 1.11-1.17 (m, 2H),0.87-0.94 (m, 2H). LC-MS: m/z 444.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(Compound 241)

¹H NMR (CHLOROFORM-d) δ 7.17 (s, 2H), 7.16 (d, J=1.8 Hz, 2H), 4.90 (br.s., 0.51H), 4.53 (d, J=13.3 Hz, 0.5H), 4.03-4.22 (m, 3H), 3.79 (br. s.,0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.52-3.63 (m, 0.5H), 3.38 (s, 3H),3.16-3.25 (m, 1H), 2.92-3.08 (m, 1H), 2.64-2.79 (m, 1H), 2.51-2.63 (m,1H), 2.18 (s, 3H), 1.56-1.63 (m, 1H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d,J=6.5 Hz, 1.5H), 1.03-1.09 (m, 2H), 0.79-0.84 (m, 2H). LC-MS: m/z 437.2(M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-m-tolylnicotinonitrile(Compound 243)

¹H NMR (DMSO-d₆) δ 7.36 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H),6.97-7.04 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.3 Hz, 0.5H), 4.24(br. s., 0.5H), 4.03-4.19 (m, 2H), 3.76 (s, 0.5H), 3.75 (s, 2H),3.55-3.64 (m, 0.5H), 3.40 (s, 3H), 3.11-3.26 (m, 1H), 2.93-3.08 (m, 1H),2.68-2.80 (m, 1H), 2.61 (d, J=11.0 Hz, 1H), 2.42 (s, 3H), 2.20 (s, 3H),1.62-1.71 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.34 (d, J=6.0 Hz, 1.5H),1.01-1.11 (m, 2H), 0.80-0.85 (m, 2H). LC-MS: m/z 433.3 (M+H)⁺.

(R)-6-cyclopropyl-5-(3-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(Compound 251)

¹H NMR (CHLOROFORM-d) δ 7.37 (t, J=7.8 Hz, 1H), 6.93 (dd, J=8.3, 2.5 Hz,1H), 6.78 (d, J=7.5 Hz, 1H), 6.74 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d,J=12.8 Hz, 0.5H), 3.96-4.21 (m, 3H), 3.83 (s, 3H), 3.71-3.77 (m, 2H),3.52-3.63 (m, 1H), 3.37 (s, 3H), 3.09-3.25 (m, 1H), 2.89-3.04 (m, 1H),2.63-2.79 (m, 1H), 2.59 (br. s., 1H), 2.16-2.29 (m, 3H), 1.63-1.72 (m,1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.29-1.33 (m, 1.5H), 1.06 (d, J=7.3 Hz,2H), 0.78-0.84 (m, 2H). LC-MS: m/z 449.3 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(4-(trifluoromethoxy)-phenyl)nicotinonitrile(Compound 255)

¹H NMR (CHLOROFORM-d) δ 7.31-7.36 (m, J=8.0 Hz, 2H), 7.23-7.28 (m, J=8.3Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.8 Hz, 0.5H), 4.01-4.22 (m,2.5H), 3.69-3.85 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.36-3.43 (m, 3H),3.12-3.28 (m, 1.5H), 2.94-3.12 (m, 1H), 2.66-2.83 (m, 1H), 2.61 (br. s.,1H), 2.16-2.22 (m, 3H), 1.54-1.65 (m, 1H), 1.39-1.46 (m, 1.5H), 1.32 (d,J=6.3 Hz, 1.5H), 1.03-1.12 (m, 2H), 0.80-0.89 (m, 2H). LC-MS: m/z 503.3(M+H)⁺.

6-cyclopropyl-5-(2,4-difluorophenyl)-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-nicotinonitrile(Compound 256)

¹H NMR (CHLOROFORM-d) δ 7.16-7.25 (m, 1H), 6.93-7.07 (m, 2H), 4.92 (br.s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.03-4.30 (m, 2.5H), 3.71-3.86 (m,2.5H), 3.51-3.67 (m, 0.5H), 3.40 (s, 3H), 3.12-3.30 (m, 1.5H), 2.95-3.11(m, 1H), 2.73 (td, J=15.3, 7.3 Hz, 1H), 2.54-2.64 (m, 1H), 2.18-2.25 (m,3H), 1.53-1.61 (m, 1H), 1.39-1.47 (m, 1.5H), 1.32 (t, J=5.8 Hz, 1.5H),1.03-1.17 (m, 2H), 0.82-0.93 (m, 2H). LC-MS: m/z 455.4 (M+H)⁺.

(R)-6-cyclopropyl-5-(3-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(Compound 257)

¹H NMR (CHLOROFORM-d) δ 7.41-7.51 (m, 1H), 7.12 (td, J=8.5, 2.5 Hz, 1H),7.01 (d, J=7.5 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.92 (br. s., 0.5H),4.55 (d, J=12.8 Hz, 0.5H), 4.04-4.22 (m, 2.5H), 3.72-3.84 (m, 2.5H),3.53-3.67 (m, 0.5H), 3.40 (s, 3H), 3.12-3.29 (m, 1.5H), 2.93-3.11 (m,1H), 2.66-2.83 (m, 1H), 2.61 (d, J=6.3 Hz, 1H), 2.16-2.25 (m, 3H),1.57-1.64 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H),1.08 (t, J=4.6 Hz, 2H), 0.80-0.91 (m, 2H). LC-MS: m/z 437.4 (M+H)⁺.

(R)-6-cyclopropyl-5-(3-fluoro-4-methylphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(Compound 258)

¹H NMR (CHLOROFORM-d) δ 7.23-7.33 (m, 2H), 6.89 (s, 1H), 6.87 (d, J=3.5Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.23 (br. s.,1H), 4.01-4.21 (m, 1.5H), 3.70-3.84 (m, 2.5H), 3.50-3.66 (m, 0.5H), 3.39(s, 3H), 3.10-3.28 (m, 1.5H), 2.92-3.09 (m, 1H), 2.65-2.81 (m, 1H),2.53-2.64 (m, 1H), 2.32-2.39 (m, 3H), 2.20 (s, 3H), 1.60-1.70 (m, 1H),1.39-1.47 (m, 1.5H), 1.30-1.35 (m, 1.5H), 1.07 (t, J=4.6 Hz, 2H), 0.83(dt, J=7.5, 3.5 Hz, 2H). LC-MS: m/z 451.4 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(napthalen-2-yl)nicotinonitrile(Compound 259)

¹H NMR (DMSO-d₆) δ 7.96 (d, J=8.5 Hz, 1H), 7.91-7.95 (m, 1H), 7.88 (dd,J=6.1, 3.4 Hz, 1H), 7.71 (s, 1H), 7.53-7.59 (m, 2H), 7.34 (dd, J=8.4,1.4 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d, J=13.3 Hz, 0.5H), 4.05-4.32(m, 3H), 3.83 (br. s., 0.5H), 3.77 (t, J=6.3 Hz, 2H), 3.56-3.67 (m,0.5H), 3.41 (s, 3H), 3.17-3.29 (m, 1H), 2.96-3.12 (m, 1H), 2.67-2.83 (m,1H), 2.55-2.65 (m, 1H), 2.23 (s, 3H), 1.63-1.71 (m, 1H), 1.45 (d, J=5.8Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.05-1.14 (m, 2H), 0.77-0.83 (m,2H). LC-MS: m/z 469.4 (M+H)⁺.

(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-3,4′-bipyridine-5-carbonitrile(Compound 260)

¹H NMR (DMSO-d₆) δ 8.87 (br. s., 2H), 7.86 (br. s., 2H), 4.94 (br. s.,0.5H), 4.71 (s, 0.5H), 4.31-4.35 (s, 3H), 3.82 (br. s., 0.5H), 3.71-3.79(m, 2H), 3.58 (br. s., 0.5H), 3.40 (s, 3H), 3.21 (br. s., 1H), 3.14 (br.s., 1H), 2.68 (br. s., 1H), 2.61 (br. s., 1H), 2.04 (br. s., 1H), 1.45(d, J=5.8 Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.05-1.14 (m, 2H),0.77-0.83 (m, 2H). LC-MS: m/z 420.5 (M+H)⁺.

(R)-5-(benzo[d][1,3]dioxol-5-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(Compound 261)

¹H NMR (DMSO-d₆) δ 6.91 (d, J=8.0 Hz, 1H), 6.62-6.71 (m, 2H), 6.03-6.10(m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.6 Hz, 0.5H), 4.03-4.24 (m,3H), 3.80 (br. s., 0.5H), 3.76 (t, J=6.1 Hz, 2H), 3.59 (t, J=11.7 Hz,0.5H), 3.39 (s, 3H), 3.18-3.25 (m, 1H), 2.92-3.08 (m, 1H), 2.65-2.80 (m,1H), 2.54-2.65 (m, 1H), 2.22 (s, 3H), 1.68-1.77 (m, 1H), 1.42 (d, J=6.5Hz, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 1.06 (t, J=5.3 Hz, 2H), 0.84 (t,J=6.1 Hz, 2H) LC-MS: m/z 463.3 (M+H)⁺.

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(thiophen-3-yl)nicotinonitrile(Compound 262)

¹H NMR (DMSO-d₆) δ 7.47 (dd, J=5.0, 3.0 Hz, 1H), 7.17 (dd, J=2.8, 1.3Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H), 4.91 (br. s., 0.5H), 4.55 (d,J=10.8 Hz, 0.5H), 3.98-4.27 (m, 3H), 3.75 (q, J=6.0 Hz, 2.5H), 3.53-3.63(m, 0.5H), 3.40 (s, 3H), 3.11-3.25 (m, 1H), 2.94-3.06 (m, 1H), 2.69-2.81(m, 1H), 2.67 (d, J=7.3 Hz, 1H), 2.25 (s, 3H), 1.71-1.78 (m, 1H), 1.42(d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.06-1.08 (m, 2H),0.83-0.88 (m, 2H). LC-MS: m/z 425.3 (M+H)⁺.

Example 5 Preparation of(R)-5-benzyl-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 239)

A mixture of the bromide 7 from Example 1 (20 mg, 0.049 mmol) andPdCl₂(dppf) CH₂Cl₂ (4 mg, 0.005 mmol) in 1 mL of dry THF was stirred atroom temperature for 5 min under nitrogen atmosphere. Benzyl zincbromide (2 mL of 0.5M solution in THF, 0.098 mmol) was then added via atransfer needle, and the resulting reaction mixture was then refluxedfor 4 h before the volatile was evaporated under reduced pressure. Theblack solid was applied to the top of a flash silica gel column, whichwas eluted with CH₂Cl₂ and then 8:1 CH₂Cl₂-EtOAc to obtain 5.1 mg ofCompound 239 as a reddish solid. MS (ES) M+H expected 421.3, found421.2. ¹H NMR (CHLOROFORM-d) δ 7.43 (s, 1H), 7.28-7.36 (m, 2H),7.19-7.25 (m, 1H), 7.08 (d, J=7.0 Hz, 2H), 4.90 (br. s., 0.5H), 4.53 (d,J=13.6 Hz, 0.5H), 4.16-4.36 (m, 3H), 3.91 (s, 2H), 3.79 (br. s., 0.5H),3.73 (t, J=6.5 Hz, 2H), 3.51-3.61 (m, 0.5H), 3.37 (s, 3H), 3.22-3.30 (m,1H), 3.12-3.21 (m, 1H), 2.63-2.78 (m, 1H), 2.51-2.61 (m, 1H), 1.38 (d,J=5.8 Hz, 1.5H), 1.28-1.32 (m, 1.5H), 1.12 (d, J=6.5 Hz, 6H). OtherCompounds of Formula II listed below, wherein R^(1b) is alkyl, —CH₂-arylor —CH₂-heteroaryl; and R² is isopropyl or cyclopropyl were similarlyprepared using any of intermediates 7 (Scheme 1), 17 (Scheme 2), or 28(Scheme 3) as starting material.

(R)-5-benzyl-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(Compound 245)

¹H NMR (CHLOROFORM-d) δ 7.29-7.35 (m, 2H), 7.24 (d, J=7.5 Hz, 1H), 7.09(d, J=7.3 Hz, 2H), 4.91 (br. s., 0.5H), 4.54 (d, J=14.1 Hz, 0.5H), 4.22(br. s., 0.5H), 4.16 (s, 2H), 4.09 (d, J=15.6 Hz, 1.5H), 3.97-4.05 (m,1H), 3.69-3.82 (m, 2H), 3.53-3.63 (m, 1H), 3.36-3.42 (m, 3H), 3.15 (t,J=13.9 Hz, 1H), 2.90-3.05 (m, 1H), 2.66-2.81 (m, 1H), 2.54-2.63 (m, 1H),2.40 (s, 3H), 2.04 (dd, J=8.0, 4.8 Hz, 1H), 1.42 (d, J=6.8 Hz, 1.5H),1.35 (br. s., 1.5H), 1.07-1.15 (m, 2H), 0.90-0.92 (m, 2H). LC-MS: m/z433.3 (M+H)⁺.

Example 6 Preparation of(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(methyl(2-(methylamino)ethyl)amino)nicotinonitrile(Compound 238)

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(methyl(2-(methylamino)ethyl)amino)nicotinonitrile(Compound 238) was prepared by mixing bromide 7 (30 mg, 0.074 mmol), CuI(0.7 mg, 0.004 mmol), K₂CO₃ (20 mg, 0.147 mmol), and N1,N2-dimethylethane-1,2-diamine (3.25 mg, 0.035 mmol) in a 5 mL microwavetube capped with a rubber septum. The tube was placed under vacuum andrefilled with nitrogen three times. Piperidine (19 mg, 0.22 mmol) andDMSO (1 mL) were added to the tube and the rubber septum was quicklyreplaced with microwave tube cap. The reaction was heated in an oil bathat 120° C. overnight before it was cooled, diluted with EtOAc, andfiltered through a pad of Celite. The EtOAc was removed on a rotaryevaporator. Compound 238 was obtained in 10 mg of quantity viapreparative TLC (DCM: MeOH/10:1) separation. MS (ES) M+H expected 417.3,found 417.5. ¹H NMR (CHLOROFORM-d) δ 7.56 (s, 1H), 4.91 (br. s., 0.5H),4.53 (d, J=12.3 Hz, 6.5H), 4.02-4.31 (m, 3H), 3.67-3.83 (m, 3H),3.47-3.64 (m, 2H), 3.34-3.41 (m, 3H), 3.16-3.30 (m, 1H), 2.93-3.13 (m,4H), 2.74-2.84 (m, 2H), 2.61 (s, 3H), 2.53 (s, 3H), 1.39 (d, J=5.8 Hz,1.5H), 1.30-1.34 (m, 1.5H), 1.17 (d, J=6.5 Hz, 6H).

Example 7 Preparation of(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrilewas prepared according to Scheme 4.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(30)

To a solution of(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7; 747 mg, 1.8 mmol) in DMF (8 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2, T-bi(1,3,2 dioxaborolane) (563 mg, 2.2mmol) and KOAc (538 mg, 5.5 mmol). The resulting mixture was stirred atroom temperature for 5 min before addition of PdCl₂(dppf). CH₂Cl₂ (45mg, 0.03 mmol). After flushing with nitrogen, the reaction mixture washeated at 85° C. for 18 hours. LC-MS analysis indicated startingmaterial still present, the temperature was raised to 120° C. andstirred overnight. After cooling, the reaction mixture was diluted withwater, and extracted with methylene chloride. The organic layer was thenwashed with brine, dried over anhy. Na₂SO₄, and concentrated in vacuo.Column chromatography (25% EtOAc/petroleum ether) afforded 334 mg of 30as a white solid. MS (ES) M+H expected 457.3, found 457.4. ¹H NMR(CHLOROFORM-d) δ 8.16 (s, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=12.3 Hz,0.5H), 4.19-4.39 (m, 3H), 3.76-3.85 (m, 0.5H), 3.73 (t, J=6.4 Hz, 2H),3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m, 1H), 3.02-3.20 (m, 1H),2.63-2.80 (m, 1H), 2.51-2.61 (m, 1H), 1.45 (d, J=7.0 Hz, 1.5H), 1.35 (d,J=6.3 Hz, 1.5H), 1.34 (s, 12H), 1.19-1.21 (dd, J=6.8, 2.0 Hz, 3H),1.23-1.25 (d, J=6.8 Hz, 3H).

(R)-5-azido-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(31)

To a solution of above boronate 30 (10 mg, 0.022 mmol) and Cu(OAc)₂.H₂O(0.5 mg, 0.0025 mmol) in MeOH (0.2 mL) was added slowly NaN₃ (2.4 mg,0.037 mmol) with stirring. After the addition, the reaction mixture washeated to 50° C. and stirred overnight. After cooling and dilution withwater, the reaction mixture was extracted with methylene chloride. Theorganic layer was then washed with brine, dried over anhy. Na₂SO₄, andconcentrated in vacuo. Column chromatography (25% ethylacetate/petroleum ether) afforded 3.7 mg of 31 as a yellowish solid. MS(ES) M+H expected 372.2, found 372.3.

—(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(32)

To a solution of above azide 31 (10 mg, 0.027 mmol) in 1 mL of MeOH wasadded 10% Pd/C (0.5 mg). The resulting mixture was purged with hydrogenand stirred at room temperature for 1 h under hydrogen atmosphere. AfterLC-MS analysis showed the formation of desired product, the reactionmixture was filtered, the filtrate was concentrated in vacuo. Columnchromatography (25% EtOAc/petroleum ether) afforded 9 mg of 32 as a pinksolid. MS (ES) M+H expected 346.2, found 346.1. ¹H NMR (CHLOROFORM-d) δ7.25 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H), 4.20 (br.s., 1H), 3.95-4.07 (m, 1H), 3.93 (br. s., 1H), 3.75 (br. s., 0.5H), 3.73(t, J=6.4 Hz, 2H), 3.52-3.63 (m, 0.5H), 3.37 (s, 3H), 3.02-3.21 (m, 2H),2.88-3.02 (m, 1H), 2.62-2.78 (m, 1H), 2.59 (t, J=5.8 Hz, 1H), 1.41 (d,J=5.8 Hz, 1.5H), 1.31-1.32 (m, 1.5H), 1.26 (s, 6H).

Example 8 Preparation of(R)-5-(benzyloxy)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 254)

Compound 254 was prepared according to general Scheme 5, below:

wherein R^(c) is —CH₂-aryl or —CH₂-heteroaryl.

Step K-1:(R)-5-hydroxy-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile

To a solution of boronate 30 from Example 7 (30 mg, 0.066 mmol) in 15 mLof THF, at room temperature, was added aq. NaOH solution (2.86 g, 0.07mmol). After stirring for 5 min, a solution of 30% of H₂O₂ (2.43 mg,0.07 mmol) was added. The reaction mixture was allowed to stir at roomtemperature for additional 30 min before it was adjusted to neutral pHand concentrated in vacuo. Column chromatography (50% EtOAc/petroleumether) afforded 21 mg of 33. MS (ES) M+H expected 347.2, found 347.3. ¹HNMR (METHANOL-d₄) δ 7.26 (s, 1H), 4.82 (br. s., 0.5H), 4.47 (d, J=13.1Hz, 0.5H), 4.39 (br. s., 0.5H), 3.95 (d, J=13.1 Hz, 0.5H), 3.79-3.92 (m,2H), 3.55-3.74 (m, 3H), 3.36 (s, 3H), 3.10-3.23 (m, 1H), 2.95-3.10 (m,1H), 2.81-2.93 (m, 1H), 2.71-2.81 (m, 1H), 2.59-2.69 (m, 1H), 1.45 (d,J=6.8 Hz, 1.5H), 1.36 (br. s., 1.5H), 1.23 (d, J=6.8 Hz, 6H).

Step K-2:(R)-5-(benzyloxy)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 254)

To a solution of(R)-5-hydroxy-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile(33; 15 mg, 0.043 mmol) in 1 mL of THF was added 60% NaH (2.1 mg, 0.052mmol) at 0° C. After stirring at room temperature for 30 min, benzylbromide (8.9 mg, 0.052 mmol) was then added. The reaction mixture wasstirred at 0° C. for 30 min and then at room temperature overnight.After the reaction mixture was concentrated, preparative TLC separationof the crude (50% ethyl acetate/petroleum ether) afforded 6.5 mg ofCompound 254 as a yellowish solid. MS (ES) M+H expected 437.3, found437.4. ¹H NMR (CHLOROFORM-d) δ 7.33-7.43 (m, 5H), 7.23 (s, 1H), 5.02 (s,2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.21 (br. s.,0.5H), 4.02-4.09 (m, 1H), 3.90-4.02 (m, 1H), 3.65-3.85 (m, 3H),3.51-3.61 (m, 0.5H), 3.42-3.51 (m, 1H), 3.37 (s, 3H), 3.09-3.23 (m, 1H),2.91-3.07 (m, 1H), 2.63-2.78 (m, 1H), 2.51-2.62 (m, 1H), 1.40 (d, J=6.5Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 6H).

Other Compounds of Formula II listed below, wherein R^(1b) is—O—CH₂-aryl or —O—CH₂-heteroaryl; and R² is isopropyl or cyclopropylwere similarly prepared according to Scheme 5 by replacing(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile30 with alternate boronates prepared from any of intermediates 7 (Scheme1), 17 (Scheme 2), or 28 (Scheme 3) using similar procedures set forthin Example 7 to prepare 30.

(R)-5-(benzyloxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 254)

1H NMR (CHLOROFORM-d) δ 7.33-7.43 (m, 5H), 7.23 (s, 1H), 5.02 (s, 2H),4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.21 (br. s., 0.5H),4.02-4.09 (m, 1H), 3.90-4.02 (m, 1H), 3.65-3.85 (m, 3H), 3.51-3.61 (m,0.5H), 3.42-3.51 (m, 1H), 3.37 (s, 3H), 3.09-3.23 (m, 1H), 2.91-3.07 (m,1H), 2.63-2.78 (m, 1H), 2.51-2.62 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H),1.31 (d, J=6.5 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 6H). LC-MS: m/z 437.4(M+H)⁺.

Example 9 Preparation of(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5-phenylnicotinonitrile(Compound 164)

Compound 164 (45, wherein m is 1; R³ is 3-methyl; and R⁸ is2-methylfuran-3-yl) was prepared according to the general scheme setforth below in general Scheme 6.

Step R: 1-(dimethylamino)-4-methyl-2-phenylpent-1-en-3-one (41)

To a solution of 3-methyl-1-phenylbutan-2-one (40; 3.38 g, 20 mmol) in40 mL of anhydrous DMF was added 1,1-dimethoxy-N,N-dimethylmethanamine(5.958 g, 50 mmol). The resulting mixture was stirred at 100° C.overnight. After removal of DMF and excess of acetal, 4.3 g of 41 wasobtained as a crude product and used in subsequent reaction withoutfurther purification. MS (ES) M+H expected 218.2, found 218.0.

Step S: 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile (42)

To a 20 mL of anhydrous DMF solution containing 960 mg of sodium hydride(22 mmol, 60% dispersion in mineral oil) was added dropwise a solutionof crude 1-(dimethylamino)-4-methyl-2-phenylpent-1-en-3-one (41; 4.3 g,20 mmol DMF solution), cyano acetamide (1.72 g, 20 mmol), and 2 mL ofMeOH in 35 mL of DMF. After the addition was completed, the resultingmixture was stirred at 80° C. overnight. After removal of DMF underreduced pressure, the residue was re-dissolved in methylene chloride andwashed with water, and brine. The organic layer was then dried overanhy. Na₂SO₄ and concentrated in vacuo. Flash column chromatography(1:10 ethyl acetate/petroleum ether) afforded 3.84 g of 42 as a whitesolid. MS (ES) M+H expected 239.1, found 239.0. ¹H NMR (DMSO-d₆) δ 8.03(s, 1H), 7.43-7.50 (m, 2H), 7.37-7.43 (m, 1H), 7.30-7.33 (m, 1H), 7.29(s, 1H), 2.85-2.97 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).

Step T. 2-chloro-6-isopropyl-5-phenylnicotinonitrile (43)

A mixture of 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile (42; 2.3 g,10 mmol), 5 mL of phosphoryl trichloride and one drop of DMF were heatedto reflux overnight until LC-MS indicated the complete conversion to theproduct. After evaporation of excess of phosphoryl trichloride underreduced pressure, the residue was re-dissolved in methylene chloride andneutralized carefully with satd. aq. NaHCO₃ and washed subsequently with1N HCl and brine. The combined organic layer was dried over anhy. Na₂SO₄and concentrated in vacuo. Flash column chromatography (1:5 ethylacetate/petroleum ether) afforded 2.4 g of 43 as a yellowish solid. MS(ES) M+H expected 257.1, found 257.0. ¹H NMR (CHLOROFORM-d) δ 7.76-7.82(m, 1H), 7.43-7.54 (m, 3H), 7.28 (br. s., 1H), 7.22-7.26 (m, 1H), 3.20(spt, J=6.7 Hz, 1H), 1.22 (s, 3H), 1.20 (s, 3H).

Step U:(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-5-phenylnicotinonitrile (44)

A mixture of above chloride 43 (192.5 mg, 0.75 mmol),(R)-2-methylpiperazine (187.8 mg, 1.875 mmol), and triethylamine (0.261mL, 1.875 mmol) suspended in 2 mL of acetonitrile was subjected tomicrowave reaction at 175° C. for 45 min. After the reaction mixture wasconcentrated in vacuo, the residue was purified by flash columnchromatography to give 184 mg of 44 as yellowish oil. MS (ES) M+Hexpected 321.2, found 321.1. ¹H NMR (CHLOROFORM-d) δ 7.56-7.66 (m, 1H),7.34-7.51 (m, 3H), 7.19-7.28 (m, 2H), 4.31-4.59 (m, 2H), 3.11-3.27 (m,3H), 3.01-3.11 (m, 2H), 2.84 (dd, J=12.8, 10.3 Hz, 1H), 1.22 (d, J=6.3Hz, 3H), 1.15 (dd, J=6.7, 1.1 Hz, 6H).

Step V:(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5-phenylnicotinonitrile(Compound 164)

In a 5-mL of amber glass vial was placed(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-5-phenyl-nicotinonitrile (50mg, 0.156 mmol), 2-methylfuran-3-carboxylic acid (39 mg, 0.312 mmol),EDCI (60 mg, 0.312 mmol), HOBt (42 mg, 0.312 mmol), triethylamine (40mg, 0.312 mmol) and 2 mL of methylene chloride. The resulting reactionmixture was stirred at room temperature overnight. The mixture wasquenched with 1 N HCl aqueous solution, extracted with EtOAc threetimes. The combined organic layer was washed with satd. NaHCO₃ andbrine, dried over anhy. Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified by preparative TLC (EtOAc: petroleum ether/100:20)to afford 28 mg of the title compound as a white solid. MS (ES) M+Hexpected 429.2, found 429.1. ¹H NMR (METHANOL-d₄) δ 7.59-7.67 (m, 1H),7.37-7.50 (m, 3H), 7.31 (d, J=2.0 Hz, 1H), 7.21-7.28 (m, 2H), 6.39 (d,J=2.0 Hz, 1H), 4.70 (br. s., 1H), 4.29-4.50 (m, 2H), 4.23 (br. s., 1H),3.49 (br. s., 1H), 3.33 (dd, J=12.9, 3.1 Hz, 1H), 3.08-3.23 (m, 2H),2.40-2.47 (m, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.16 (dd, J=6.8, 2.8 Hz, 6H).

Other Compounds of Formula II listed below, wherein R^(1a) is hydrogen;R^(1b) is optionally substituted phenyl; were similarly preparedaccording to Scheme 6 by replacing one or more of: (1)methyl-1-phenylbutan-2-one (40) with an alternate phenyl ketone asstarting material; (2) (R)-2-methylpiperazine with an alternatepiperazine in Step U; and (3) 2-methylfuran-3-carboxylic acid with analternate acid in Step V.

2-(4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 109)

¹H NMR (CHLOROFORM-d) δ 7.65 (s, 1H), 7.53-7.58 (m, 1H), 7.38-7.49 (m,3H), 7.24-7.28 (m, 2H), 7.10 (d, J=3.3 Hz, 1H), 6.54 (dd, J=3.3, 1.8 Hz,1H), 4.03 (br. s., 4H), 3.89 (dd, J=6.4, 3.6 Hz, 4H), 3.17 (dt, J=13.4,6.7 Hz, 1H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z 401.1 (M+H)⁺.

2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 119)

¹H NMR (CHLOROFORM-d) δ 7.62-7.69 (m, 1H), 7.54 (d, J=0.8 Hz, 1H),7.40-7.47 (m, 3H), 7.23-7.28 (m, 2H), 7.08 (d, J=3.5 Hz, 1H), 6.53 (dd,J=3.5, 1.8 Hz, 1H), 4.93 (br. s., 1H), 4.54 (d, J=12.8 Hz, 1H), 4.45 (d,J=12.3 Hz, 1H), 4.37 (d, J=13.3 Hz, 1H), 3.58 (br. s., 1H), 3.44 (dd,J=13.3, 3.8 Hz, 1H), 3.27 (td, J=12.4, 3.4 Hz, 1H), 3.16 (dt, J=13.3,6.7 Hz, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.7, 1.9 Hz, 6H).LC-MS: m/z 414.9 (M+H)⁺.

2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 120)

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.64 (s, 1H), 7.40-7.51 (m, 4H),7.24-7.28 (m, 2H), 6.61 (d, J=1.3 Hz, 1H), 4.76 (br. s., 1H), 4.33-4.52(m, 3H), 3.51 (s, 1H), 3.35 (dd, J=13.2, 3.1 Hz, 1H), 3.12-3.22 (m, 2H),1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.5, 2.0 Hz, 6H). LC-MS: m/z 414.9(M+H)⁺.

2-(4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 124)

¹H NMR (CHLOROFORM-d) δ 7.76-7.81 (m, 1H), 7.65 (s, 1H), 7.36-7.51 (m,4H), 7.23-7.28 (m, 2H), 6.62 (dd, J=1.9, 0.9 Hz, 1H), 3.91 (br. s., 4H),3.84 (br. s., 4H), 3.17 (dt, J=13.4, 6.6 Hz, 1H), 1.17 (d, J=6.8 Hz,6H). LC-MS: m/z 401.1 (M+H)⁺.

2-(4-(1H-indole-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 125)

¹H NMR (CHLOROFORM-d) δ 8.97 (br. s., 1H), 7.74-7.81 (m, 1H), 7.64 (s,1H), 7.53 (br. s., 1H), 7.38-7.50 (m, 4H), 7.28-7.31 (m, 1H), 7.24-7.28(m, 3H), 3.94 (br. s., 4H), 3.85 (br. s., 4H), 3.16 (dt, J=13.2, 6.6 Hz,1H), 1.17 (d, J=6.5 Hz, 6H). LC-MS: m/z 450.2 (M+H)⁺.

6-isopropyl-5-phenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)nicotinonitrile(Compound 126)

¹H NMR (CHLOROFORM-d) δ 7.62 (s, 1H), 7.41-7.47 (m, 3H), 7.38-7.41 (m,1H), 7.37 (s, 1H), 7.34-7.36 (m, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.25(d, J=1.5 Hz, 1H), 7.24 (s, 1H), 3.84-3.89 (m, 2H), 3.83 (s, 2H),3.73-3.78 (m, 2H), 3.64-3.68 (m, 2H), 3.58-3.63 (m, 2H), 3.15 (dt,J=13.3, 6.7 Hz, 1H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 425.1 (M+H)⁺.

6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-5-phenylnicotinonitrile(Compound 139)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.37-7.51 (m, 4H), 7.33-7.37 (m,2H), 7.29-7.33 (m, 2H), 7.22-7.27 (m, 2H), 4.62 (d, J=13.6 Hz, 0.5H),4.42 (d, J=12.5 Hz, 0.5H), 4.19-4.35 (m, 2H), 3.81 (br. s., 1H), 3.76(d, J=13.1 Hz, 0.5H), 3.49 (t, J=12.0 Hz, 0.5H), 2.91-3.29 (m, 3H), 1.31(br. s., 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 439.2 (M+H)⁺.

2-((3S,5R)-3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 140)

¹H NMR (CHLOROFORM-d) δ 7.61-7.64 (m, 1H), 7.41-7.48 (m, 3H), 7.38-7.41(m, 1H), 7.37 (s, 1H), 7.34-7.36 (m, 1H), 7.32 (s, 1H), 7.30 (s, 1H),7.27 (d, J=1.8 Hz, 1H), 7.23-7.26 (m, 1H), 4.90 (br. s., 1H), 4.46 (br.s., 2H), 4.20 (br. s., 1H), 3.82 (s, 2H), 3.12-3.22 (m, 2H), 3.11 (br.s., 1H), 1.43 (d, J=7.0 Hz, 6H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z453.1 (M+H)⁺.

2-((3S,5R)-4-(furan-3-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 141)

¹H NMR (CHLOROFORM-d) δ 7.77 (dd, J=1.5, 0.8 Hz, 1H), 7.65 (s, 1H),7.47-7.49 (m, 1H), 7.45-7.47 (m, 1H), 7.44 (s, 1H), 7.40-7.43 (m, 1H),7.24-7.28 (m, 2H), 6.65 (dd, J=1.9, 0.9 Hz, 1H), 4.71 (br. s., 2H), 4.47(s, 1H), 4.50 (s, 1H), 3.27 (dd, J=12.9, 4.1 Hz, 2H), 3.18 (dt, J=13.3,6.7 Hz, 1H), 1.55 (d, J=7.0 Hz, 6H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z429.2 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-5-phenylnicotinonitrile(Compound 143)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.39-7.47 (m, 3H), 7.34-7.39 (m,2H), 7.29-7.33 (m, 2H), 7.22-7.28 (m, 3H), 4.98 (br. s., 0.5H), 4.62 (d,J=13.8 Hz, 0.5H), 4.42 (d, J=12.0 Hz, 0.5H), 4.15-4.35 (m, 2H), 3.81(br. s., 2H), 3.72-3.79 (m, 0.5H), 3.49 (t, J=11.3 Hz, 0.5H), 3.29 (d,J=10.0 Hz, 0.5H), 3.04-3.21 (m, 2.5H), 2.88-3.01 (m, 0.5H), 1.27-1.34(m, 3H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 439.2 (M+H)⁺.

(S)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 144)

¹H NMR (CHLOROFORM-d) δ 7.74-7.80 (m, 1H), 7.64 (s, 1H), 7.36-7.52 (m,4H), 7.27 (dd, J=7.9, 6.4 Hz, 2H), 6.59-6.64 (m, 1H), 4.76 (br. s., 1H),4.20-4.50 (m, 3H), 3.51 (br. s., 1H), 3.35 (dd, J=13.3, 3.3 Hz, 1H),3.06-3.24 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.5, 2.0 Hz, 6H).LC-MS: m/z 415.2 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-5-phenylnicotinonitrile(Compound 145)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.29-7.47 (m, 7H), 7.22-7.28 (m,3H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.6 Hz, 0.5H), 4.42 (d, J=12.8 Hz,0.5H), 4.15-4.37 (m, 2H), 3.80-3.85 (m, 2H), 3.76 (d, J=12.8 Hz, 0.5H),3.49 (t, J=11.2 Hz, 0.5H), 3.25-3.37 (m, 0.5H), 3.02-3.23 (m, 2.5H),2.88-3.01 (m, 0.5H), 1.26-1.35 (m, 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS:m/z 439.2 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 150)

¹H NMR (CHLOROFORM-d) δ 7.77 (dd, J=1.5, 1.0 Hz, 1H), 7.63-7.66 (m, 1H),7.38-7.50 (m, 4H), 7.23-7.28 (m, 2H), 6.61 (dd, J=1.8, 0.8 Hz, 1H), 4.76(br. s., 1H), 4.30-4.51 (m, 3H), 3.52 (br. s., 1H), 3.35 (dd, J=13.2,3.6 Hz, 1H), 3.06-3.24 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.8,2.0 Hz, 6H). LC-MS: m/z 415.1 (M+H)⁺.

2-(4-(furan-3-carbonyl)-3-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 153)

¹H NMR (CHLOROFORM-d) δ 7.59-7.74 (m, 1H), 7.56 (s, 1H), 7.33-7.50 (m,8H), 7.29 (d, J=7.3 Hz, 1H), 7.17-7.25 (m, 2H), 6.54 (br. s., 1H), 5.74(br. s., 1H), 4.79 (br. s., 1H), 4.51 (br. s., 1H), 4.33 (d, J=9.5 Hz,1H), 3.95 (d, J=11.5 Hz, 1H), 3.58 (br. s., 2H), 3.12 (spt, J=6.6 Hz,1H), 1.08-1.18 (m, 6H). LC-MS: m/z 477.1 (M+H)⁺.

2-(4-(furan-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 159)

¹H NMR (CHLOROFORM-d) δ 7.72 (br. s., 1H), 7.48-7.60 (m, 5H), 7.46 (br.s., 3H), 7.40 (br. s., 2H), 7.27 (br. s., 1H), 7.20 (d, J=6.8 Hz, 1H),6.77 (s, 1H), 6.59 (s, 1H), 5.14-5.37 (m, 1H), 4.25 (br. s., 2H), 3.87(br. s., 3H), 3.64 (br. s., 1H), 2.81-2.95 (m, 1H), 1.16 (d, J=6.5 Hz,3H), 1.06 (d, J=6.3 Hz, 3H). LC-MS: m/z 477.2 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-phenylnicotinonitrile(Compound 165)

¹H NMR (METHANOL-d₄) δ 7.62 (s, 1H), 7.35-7.57 (m, 3H), 7.21-7.28 (m,3H), 6.87-7.11 (m, 2H), 4.60 (d, J=13.3 Hz, 1H), 4.29-4.37 (m, 2H), 3.98(s, 2H), 3.59 (t, J=11.4 Hz, 1H), 3.04-3.27 (m, 4H), 1.36 (dd, J=15.2,5.9 Hz, 3H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 445.0 (M+H)⁺.

2-(4-(furan-2-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 166)

¹H NMR (CHLOROFORM-d) δ 7.54-7.56 (m, 2H), 7.52 (br. s., 3H), 7.43 (br.s., 2H), 7.24-7.30 (m, 3H), 7.20 (d, J=7.3 Hz, 1H), 7.08 (d, J=3.3 Hz,1H), 6.77 (s, 1H), 6.52 (br. s., 1H), 5.31-5.37 (br. s., 1H), 4.40 (br.s., 1H), 4.32 (br. s., 1H), 3.85-4.03 (m, 2H), 3.79 (d, J=13.1 Hz, 1H),3.68 (d, J=4.8 Hz, 1H), 2.87 (dt, J=13.4, 6.8 Hz, 1H), 1.15 (d, J=6.8Hz, 3H), 1.06 (d, J=6.5 Hz, 3H). LC-MS: m/z 477.2 (M+H)⁺.

2-(4-(1H-indole-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 168)

¹H NMR (CHLOROFORM-d) δ 9.09 (br. s., 1H), 7.76 (br. s., 1H), 7.51 (s,2H), 7.55 (s, 3H), 7.39 (br. s., 3H), 7.29 (s, 2H), 7.33 (s, 1H), 7.24(br. s., 3H), 6.77 (br. s., 1H), 5.29 (br. s., 1H), 4.30 (d, J=11.5 Hz,1H), 4.18 (br. s., 1H), 3.93 (br. s., 3H), 3.64 (br. s., 1H), 2.89 (br.s., 1H), 1.16 (d, J=5.8 Hz, 3H), 1.07 (d, J=5.8 Hz, 3H). LC-MS: m/z526.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-isopropylpiperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 170)

¹H NMR (CHLOROFORM-d) δ 7.74 (br. s., 1H), 7.61 (s, 1H), 7.47 (t, J=1.6Hz, 1H), 7.35-7.46 (m, 3H), 7.20-7.26 (m, 2H), 6.58 (s, 1H), 4.79 (d,J=12.8 Hz, 1H), 4.54-4.68 (br. s., 1H), 4.45 (br. s., 1H), 3.8-4.07 (m,1H), 3.56-3.74 (m, 1H), 3.19 (br. s., 1H), 3.06-3.18 (m, 3H), 1.52-1.59(m, 3H), 1.40-1.48 (m, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.8 Hz,3H). LC-MS: m/z 443.1 (M+H)⁺.

(R)-2-(3-ethyl-4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 171)

¹H NMR (CHLOROFORM-d) δ 7.74 (s, 1H), 7.58-7.65 (m, 1H), 7.35-7.50 (m,4H), 7.20-7.26 (m, 2H), 6.58 (dd, J=1.8, 0.8 Hz, 1H), 5.02 (s, 1H), 4.69(br. s., 1H), 4.50 (d, J=13.1 Hz, 1H), 4.41 (d, J=12.3 Hz, 1H),4.23-4.31 (br. s., 1H), 3.46-3.86 (m, 2H), 3.27 (dd, J=13.3, 3.3 Hz,1H), 3.10-3.21 (m, 2H), 1.79-1.96 (m, 2H), 1.54 (d, J=6.5 Hz, 1.5H),1.45 (d, J=6.5 Hz, 1.5H), 1.15 (dd, J=6.8, 3.5 Hz, 6H). LC-MS: m/z 429.1(M+H)⁺.

(R)-2-(3-ethyl-4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 172)

¹H NMR (CHLOROFORM-d) δ 7.59-7.64 (m, 1H), 7.51 (dd, J=1.8, 0.8 Hz, 1H),7.36-7.46 (m, 3H), 7.21-7.26 (m, 2H), 7.02-7.10 (m, 1H), 6.51 (dd,J=3.5, 1.8 Hz, 1H), 4.71 (br. s., 1H), 4.38-4.60 (m, 3H), 3.50 (br. s.,1H), 3.35 (dd, J=13.3, 3.5 Hz, 1H), 3.22 (td, J=12.5, 3.4 Hz, 1H),3.08-3.18 (m, 1H), 1.90-2.06 (m, 1H), 1.83 (dquin, J=14.2, 7.2 Hz, 1H),1.15 (dd, J=6.7, 3.1 Hz, 6H), 0.97 (t, J=7.4 Hz, 3H). LC-MS: m/z 429.1(M+H)⁺.

(R)-2-(3-ethyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 173)

¹H NMR (CHLOROFORM-d) δ 7.58-7.66 (m, 1H), 7.35-7.47 (m, 3H), 7.29 (d,J=2.0 Hz, 1H), 7.21-7.26 (m, 2H), 6.32-6.41 (m, 1H), 4.59-4.80 (m, 1H),4.50 (d, J=13.1 Hz, 1H), 4.42 (br. s., 1H), 3.91-3.97 (br. s., 1H),3.45-3.65 (m, 1H), 3.27 (dd, J=13.1, 3.3 Hz, 1H), 3.05-3.19 (m, 2H),2.41 (s, 3H), 1.86-1.95 (m, 1H), 1.79 (dt, J=14.1, 7.0 Hz, 1H), 1.15(dd, J=6.8, 2.0 Hz, 6H), 0.87-0.99 (m, 3H). LC-MS: m/z 443.1 (M+H)⁺.

(R)-2-(3-ethyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile(Compound 174)

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.35-7.49 (m, 3H), 7.17-7.25 (m,3H), 6.92-6.99 (m, 2H), 4.75 (br. s., 0.5H), 4.59-4.71 (m, 0.5H),4.30-4.50 (m, 2H), 3.79-4.07 (m, 3H), 3.46-3.56 (m, 0.5H), 3.17-3.30 (m,0.5H), 2.97-3.17 (m, 3H), 1.78-1.89 (m, 1H), 1.69-1.78 (m, 1H),1.10-1.16 (m, 6H), 0.90-0.97 (m, 3H). LC-MS: m/z 459.1 (M+H)⁺.

2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-5,6-diphenylnicotinonitrile(Compound 117)

Compound 117 was synthesized was synthesized was synthesized using1,2-diphenylethanone as starting material.

¹H NMR (CHLOROFORM-d) δ 7.87 (s, 1H), 7.53 (dd, J=1.5, 0.8 Hz, 1H),7.37-7.44 (m, 2H), 7.27-7.35 (m, 6H), 7.12-7.19 (m, 2H), 7.06-7.12 (m,1H), 6.53 (dd, J=3.4, 1.9 Hz, 1H), 4.94 (br. s., 1H), 4.53 (t, J=11.7Hz, 2H), 4.36-4.46 (m, 1H), 3.62 (br. s., 1H), 3.44-3.54 (m, 1H),3.26-3.37 (m, 1H), 1.52 (d, J=6.5 Hz, 3H). LC-MS: m/z 448.9 (M+H)⁺.

2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-5,6-diphenylnicotinonitrile(Compound 118)

Compound 118 was synthesized using 1,2-diphenylethanone as startingmaterial.

¹H NMR (CHLOROFORM-d) δ 7.88 (s, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 7.38(d, J=8.0 Hz, 2H), 7.27-7.33 (m, 6H), 7.13-7.16 (m, 2H), 6.61 (s, 1H),4.71-4.79 (br. s., 1H), 4.47-4.50 (s, 1H), 4.38 (s, 1H), 4.41 (s, 1H),3.48-3.64 (m, 1H), 3.38-3.42 (m, 1H), 3.21 (td, J=12.4, 3.0 Hz, 1H),1.49 (d, J=6.5 Hz, 3H). LC-MS: m/z 448.9 (M+H)⁺.

2-(4-(furan-3-carbonyl)piperazin-1-yl)-5,6-diphenylnicotinonitrile(Compound 122)

Compound 122 was synthesized using 1,2-diphenylethanone as startingmaterial.

¹H NMR (CHLOROFORM-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.47-7.51 (m, 1H),7.37-7.42 (m, 2H), 7.27-7.35 (m, 6H), 7.15 (dd, J=6.5, 3.0 Hz, 2H), 6.62(s, 1H), 3.92 (br. s., 4H), 3.89 (br. s., 4H). LC-MS: m/z 435.1 (M+H)⁺.

5,6-diphenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)nicotinonitrile(Compound 123)

Compound 123 was synthesized using 1,2-diphenylethanone as startingmaterial. ¹H NMR (CHLOROFORM-d) δ 7.85 (s, 1H), 7.34-7.39 (m, 4H),7.28-7.33 (m, 8H), 7.22-7.26 (m, 1H), 7.13 (dd, J=6.5, 3.0 Hz, 2H),3.85-3.91 (m, 2H), 3.79-3.84 (m, 4H), 3.66 (s, 4H). LC-MS: m/z 459.1(M+H)⁺.

(R)-5-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 161)

Compound 161 was synthesized using1-(3-fluorophenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.73-7.79 (m, 1H), 7.61 (s, 1H), 7.47 (t, J=1.6Hz, 1H), 7.35-7.44 (m, 1H), 7.06-7.13 (m, 1H), 7.00-7.04 (m, 1H), 6.96(dt, J=9.3, 2.1 Hz, 1H), 6.54-6.63 (m, 1H), 4.61-4.90 (m, 1H), 4.41 (s,0.5H), 4.44 (s, 0.5H), 4.19-4.39 (m, 2H), 3.42-3.49 (br. s., 1H), 3.34(dd, J=13.2, 3.1 Hz, 1H), 3.14-3.23 (m, 1H), 3.06-3.14 (m, 1H), 1.44 (d,J=6.8 Hz, 3H), 1.15 (dd, J=6.8, 1.8 Hz, 6H). LC-MS: m/z 433.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(2-methoxyphenyl)nicotinonitrile(Compound 175)

Compound 175 was synthesized using1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.56 (s, 1H), 7.46 (t, J=1.5 Hz,1H), 7.34-7.41 (m, 1H), 7.06-7.12 (m, 1H), 7.01 (t, J=7.3 Hz, 1H), 6.96(d, J=8.3 Hz, 1H), 6.55-6.62 (m, 1H), 4.74 (br. s., 1H), 4.18-4.46 (m,3H), 3.77 (s, 3H), 3.49 (br. s., 1H), 3.31 (dd, J=13.2, 3.1 Hz, 1H),3.14 (td, J=12.5, 3.0 Hz, 1H), 2.86 (quin, J=6.7 Hz, 1H), 1.46 (d, J=6.8Hz, 3H), 1.15 (br. s., 3H), 1.04 (br. s., 3H). LC-MS: m/z 445.2 (M+H)⁺.

(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(2-methoxyphenyl)nicotinonitrile(Compound 176)

Compound 176 was synthesized using1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.56 (s, 1H), 7.50-7.53 (m, 1H), 7.34-7.41 (m,1H), 7.07-7.13 (m, 1H), 7.03-7.06 (m, 1H), 6.99-7.02 (m, 1H), 6.96 (d,J=8.3 Hz, 1H), 6.51 (dd, J=3.3, 1.8 Hz, 1H), 4.90 (br. s., 1H), 4.51 (d,J=13.6 Hz, 1H), 4.41 (d, J=13.8 Hz, 1H), 4.34 (d, J=13.3 Hz, 1H), 3.77(s, 3H), 3.57 (d, J=10.5 Hz, 1H), 3.39 (dd, J=13.1, 3.5 Hz, 1H), 3.23(td, J=12.4, 3.1 Hz, 1H), 2.86 (dt, J=13.3, 6.7 Hz, 1H), 1.49 (d, J=6.5Hz, 3H), 1.16 (br. s., 3H), 1.05 (br. s., 3H). LC-MS: m/z 445.2 (M+H)⁺.

(R)-6-isopropyl-5-(2-methoxyphenyl)-2-(3-methyl-4-(2-(thiophen-2-acetyl)piperazin-1-yl)nicotinonitrile(Compound 177)

Compound 177 was synthesized using1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.54 (s, 1H), 7.33-7.41 (m, 1H), 7.20-7.24 (m,1H), 7.05-7.11 (m, 1H), 6.98-7.04 (m, 1H), 6.89-6.98 (m, 3H), 4.94 (br.s., 0.5H), 4.58 (d, J=12.8 Hz, 0.2H), 4.17-4.46 (m, 3H), 3.91-4.04 (m,2H), 3.76 (s, 3H), 3.56 (t, J=11.2 Hz, 0.5H), 3.27 (d, J=12.8 Hz, 0.5H),3.13-3.23 (m, 1H), 2.98-3.11 (m, 1H), 2.85 (dt, J=13.3, 6.7 Hz, 1H),1.33-1.39 (m, 3H), 1.15 (br. s., 3H), 1.04 (br. s., 3H). LC-MS: m/z475.2 (M+H)⁺.

(R)-6-isopropyl-5-(2-methoxyphenyl)-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)nicotino-nitrile(Compound 178)

Compound 178 was synthesized using1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.52-7.59 (m, 1H), 7.34-7.41 (m, 1H), 7.29 (d,J=1.8 Hz, 1H), 7.08 (dd, J=7.3, 1.8 Hz, 1H), 7.01 (t, J=7.2 Hz, 1H),6.96 (d, J=8.3 Hz, 1H), 6.38 (d, J=1.8 Hz, 1H), 4.69 (br. s., 1H),4.29-4.43 (m, 2H), 4.00-4.29 (m, 1H), 3.77 (s, 3H), 3.46 (br. s., 1H),3.24-3.39 (m, 1H), 3.11 (td, J=12.5, 3.0 Hz, 1H), 2.86 (spt, J=6.6 Hz,1H), 2.41 (s, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.12-1.19 (m, 3H), 1.04 (br.s., 3H). LC-MS: m/z 459.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-p-tolylnicotinonitrile(Compound 179)

Compound 179 was synthesized using 3-methyl-1-p-tolylbutan-2-one asstarting material.

¹H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.60 (s, 1H), 7.44-7.49 (m, 1H),7.24 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 6.55-6.62 (m, 1H), 4.74(br. s., 1H), 4.20-4.49 (m, 3H), 3.38-3.57 (m, 1H), 3.31 (dd, J=13.1,3.0 Hz, 1H), 3.07-3.22 (m, 2H), 2.37-2.46 (m, 3H), 1.45 (d, J=6.8 Hz,3H), 1.07-1.20 (m, 6H). LC-MS: m/z 429.1 (M+H)⁺.

(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-p-tolylnicotinonitrile(Compound 180)

Compound 180 was synthesized using 3-methyl-1-p-tolylbutan-2-one asstarting material.

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.50-7.53 (m, 1H), 7.24 (d, J=7.8Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.05 (d, J=3.5 Hz, 1H), 6.46-6.55 (m,1H), 4.90 (br. s., 1H), 4.51 (d, J=13.6 Hz, 1H), 4.42 (d, J=14.1 Hz,1H), 4.33 (dt, J=13.3, 2.0 Hz, 1H), 3.57 (d, J=10.3 Hz, 1H), 3.40 (dd,J=13.2, 3.6 Hz, 1H), 3.18-3.30 (m, 1H), 3.09-3.18 (m, 1H), 2.41 (s, 3H),1.48 (d, J=6.8 Hz, 3H), 1.07-1.20 (m, 6H). LC-MS: m/z 429.2 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-p-tolylnicotinonitrile(Compound 181)

Compound 181 was synthesized using 3-methyl-1-p-tolylbutan-2-one asstarting material.

¹H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.20-7.25 (m, 3H), 7.12 (d, J=7.8Hz, 2H), 6.88-7.00 (m, 2H), 4.94 (br. s., 0.5H), 4.58 (d, J=13.1 Hz,0.5H), 4.32-4.43 (m, 1H), 4.27 (s, 1H), 4.30 (s, 1H), 3.91-4.05 (m, 2H),3.80 (d, J=13.6 Hz, 0.5H), 3.51-3.63 (m, 0.5H), 3.20-3.33 (m, 1H),3.11-3.20 (m, 1H), 2.98-3.10 (m, 1H), 2.41 (s, 3H), 1.36 (d, J=6.3 Hz,1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.13 (d, J=6.5 Hz, 6H). LC-MS: m/z459.1 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5-p-tolylnicotinonitrile(Compound 182)

Compound 182 was synthesized using 3-methyl-1-p-tolylbutan-2-one asstarting material.

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.28-7.32 (m, 1H), 7.24 (d, J=8.0Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 6.36-6.41 (m, 1H), 4.69 (br. s., 1H),4.38 (d, J=13.3 Hz, 1H), 4.33 (d, J=13.1 Hz, 1H), 4.23 (d, J=12.0 Hz,1H), 3.46 (br. s., 1H), 3.26-3.34 (m, 1H), 3.13-3.21 (m, 1H), 3.05-3.13(m, 1H), 2.41 (s, 6H), 1.41 (d, J=6.8 Hz, 3H), 1.14 (dd, J=6.7, 3.4 Hz,6H). LC-MS: m/z 443.2 (M+H)⁺.

(R)-6-isopropyl-5-(2-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 183)

Compound 183 was synthesized using1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.55 (s, 1H), 7.34-7.42 (m, 1H), 7.05-7.12 (m,1H), 6.99-7.05 (m, 1H), 6.96 (d, J=8.3 Hz, 1H), 4.93 (br. s., 0.5H),4.55 (d, J=13.1 Hz, 0.5H), 4.19-4.43 (m, 3H), 3.82 (d, J=7.5 Hz, 0.5H),3.76 (s, 3H), 3.70-3.76 (m, 2H), 3.54-3.64 (m, 0.5H), 3.38 (s, 3H), 3.30(t, J=13.3 Hz, 1H), 3.02-3.22 (m, 1H), 2.82-2.92 (m, 1H), 2.66-2.80 (m,1H), 2.53-2.65 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.5 Hz,1.5H), 1.16 (br. s., 3H), 1.05 (br. s., 3H). LC-MS: m/z 437.1 (M+H)⁺.

(S)-5-(2-ethoxyphenyl)-2-(4-(furan-2-carbonyl)-2-methylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 184)

Compound 184 was synthesized using1-(2-ethoxyphenyl)-3-methylbutan-2-one as starting material.

¹H NMR (CHLOROFORM-d) δ 7.55 (s, 1H), 7.48-7.53 (m, 1H), 7.31-7.38 (m,1H), 7.05-7.11 (m, 2H), 6.96-7.02 (m, 1H), 6.94 (d, J=8.3 Hz, 1H),6.45-6.56 (m, 1H), 4.77 (br. s., 1H), 4.53 (d, J=11.3 Hz, 1H), 4.36 (d,J=13.3 Hz, 1H), 4.23-4.33 (m, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.38-3.67 (m,3H), 2.84-2.97 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.27-1.30 (m, 3H),1.24-1.27 (m, 6H). LC-MS: m/z 459.1 (M+H)⁺.

(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-p-tolylnicotinonitrile(Compound 198)

Compound 198 was synthesized using 3-methyl-1-p-tolylbutan-2-one asstarting material.

¹H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.12 (d,J=8.0 Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.21-4.42(m, 3H), 3.81 (d, J=13.8 Hz, 0.5H), 3.69-3.77 (m, 62H), 3.53-3.64 (m,0.5H), 3.38 (s, 3H), 3.31 (t, J=12.3 Hz, 1H), 3.11-3.19 (m, 2H),2.65-2.81 (m, 1H), 2.54-2.63 (m, 1H), 2.41 (s, 3H), 1.40 (d, J=6.3 Hz,1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z421.1 (M+H)⁺.

(R)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5,6-diphenylnicotinonitrile(Compound 240)

Compound 240 was synthesized using 1,2-diphenylethanone as startingmaterial. ¹H NMR (CHLOROFORM-d) δ 7.84 (s, 1H), 7.33-7.40 (m, 2H),7.26-7.33 (m, 4H), 7.20-7.25 (m, 2H), 7.08-7.16 (m, 2H), 4.94 (br. s.,0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.38-4.49 (m, 1H), 4.23-4.38 (m, 2H),3.77-3.90 (m, 1H), 3.74 (t, J=6.0 Hz, 2H), 3.54-3.64 (m, 0.5H), 3.37 (s,3H), 3.34 (d, J=6.3 Hz, 0.5H), 3.19-3.26 (m, 1H), 3.06-3.19 (m, 1H),2.66-2.78 (m, 1H), 2.55-2.63 (m, 1H), 1.39-1.46 (m, 1.5H), 1.33 (d,J=6.0 Hz, 1.5H). LC-MS: m/z 441.3 (M+H)⁺.

Example 10 Preparation of(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 130)

Compound 130 (55, wherein m is 1, R³ is methyl; and R⁸ is furan-3-yl)was synthesized according to general Scheme 7.

Step W: 2-hydroxy-6-isopropyl-4-phenylnicotinonitrile (52)

To a suspension of ammonium acetate (31.46 g, 0.4 mol) in 200 mL of EtOHwas added successively the 3-methyl-2-butanone (51; 5.38 mL, 50 mmol),benzaldehyde (50; 5.21 g, 50 mmol), and ethyl cyanoacetate (23; 5.6 mL,50 mmol). The resulting mixture was stirred at reflux temperature for 3hrs and subsequently at room temperature overnight. After the LC-MSshowed the formation of the desired product, the precipitate formed wasfiltered and washed with EtOH (10 mL×3 times) and hexane (10 mL×3times). After air-drying, 2.18 g of 52 was obtained as a white solid. MS(ES) M+H expected 239.1, found 239.0. ¹H NMR (CHLOROFORM-d) δ 7.61-7.70(m, 2H), 7.51-7.58 (m, 3H), 6.33 (s, 1H), 3.06 (dt, J=13.8, 6.9 Hz, 1H),1.42 (d, J=7.0 Hz, 6H).

Step X: 2-chloro-6-isopropyl-4-phenylnicotinonitrile (53)

A mixture of 2-hydroxy-6-isopropyl-4-phenylnicotinonitrile 52; (0.702 g,2.94 mmol), 7 mL of phosphoryl trichloride and one drop of DMF wereheated to reflux overnight until LC-MS indicated the complete conversionto the product. After evaporation of excess of phosphoryl trichlorideunder reduced pressure, the residue was re-dissolved in methylenechloride and neutralized carefully with satd. aq. NaHCO₃ and washedsubsequently with 1N HCl and brine. The combined organic layer was driedover anhy. Na₂SO₄ and concentrated in vacuo. Flash column chromatography(1:5 ethyl acetate/petroleum ether) afforded 717 mg of 53 as a yellowishsolid. MS (ES) M+H expected 257.1, found 257.0. ¹H NMR (CHLOROFORM-d) δ7.52-7.64 (m, 5H), 7.26 (s, 1H), 3.09-3.21 (m, 1H), 1.37 (d, J=7.0 Hz,6H).

Step Y:(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-4-phenylnicotinonitrile (54)

A mixture of above chloride 53 (192.6 mg, 0.75 mmol),(R)-2-methylpiperazine (150 mg, 1.5 mmol), and triethylamine (0.21 mL,1.5 mmol) suspended in 1.5 mL of acetonitrile was subjected to microwavereaction at 175° C. for 45 min. After the reaction mixture wasconcentrated in vacuo, the residue was purified by flash columnchromatography to give 197 mg of 54 as yellowish oil. MS (ES) M+Hexpected 321.2, found 321.1. ¹H NMR (CHLOROFORM-d) δ 7.54-7.60 (m, 2H),7.47-7.53 (m, 3H), 6.71 (s, 1H), 4.21-4.35 (m, 2H), 3.03-3.18 (m, 4H),2.99 (dt, J=13.8, 6.9 Hz, 1H), 2.78 (dd, J=12.7, 10.2 Hz, 1H), 1.30 (d,J=7.0 Hz, 6H), 1.15-1.20 (m, 3H).

Step Z:(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 130)

In a 5-mL of amber glass vial was placed(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-4-phenyl-nicotinonitrile (54;32 mg, 0.1 mmol), furan-3-carboxylic acid (22.4 mg, 0.312 mmol), EDCI(38.2 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol), triethylamine (35 μL, 0.2mmol) and 1.5 mL of methylene chloride. The resulting reaction mixturewas stirred at room temperature overnight. The mixture was quenched with1 N HCl aqueous solution, extracted with EtOAc three times. The combinedorganic layer was washed with satd. NaHCO₃ and brine, dried over anhy.Na₂SO₄, and concentrated in vacuo. The crude product was purified bypreparative TLC (EtOAc: petroleum ether/20:100) to afford 23 mg ofCompound 130 as a light yellowish solid. MS (ES) M+H expected 415.2,found 415.1. ¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.55-7.58 (m, 2H),7.50-7.53 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.60-6.62 (m,1H), 4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz,1H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td, J=12.5,3.5 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.31 (d,J=6.8 Hz, 6H).

Other Compounds of Formula II listed below, wherein R^(1a) is optionallysubstituted phenyl; and R^(1b) is hydrogen; were similarly prepared bygeneral Scheme 7 replacing one or more of: (1) 3-methyl-2-butanone (51)with an alternate ketone as starting material; (2) benzaldehyde (50)with an alternate aldehyde as starting material; (3)(R)-2-methylpiperazine with an alternate piperazine in Step Y; and (4)2-methylfuran-3-carboxylic acid with an alternate acid in Step Z. Inaddition, a compound wherein R^(1a) is isopropyl; R^(1b) is hydrogen andR² is phenyl was also prepared by the same method of general Scheme 7.

2-(4-benzoylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 100)

¹H NMR (DMSO-d₆) δ 7.54-7.59 (m, 2H), 7.50-7.54 (m, 3H), 7.47 (s, 5H),6.80 (s, 1H), 4.01 (br. s., 2H), 3.74-3.89 (m, 3H), 3.66 (br. s., 3H),3.01 (quin, J=6.8 Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H). LC-MS: m/z 411.1(M+H)⁺.

2-((3S,5R)-4-benzoyl-3,5-dimethylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 101)

¹H NMR (DMSO-d₆) δ 7.53-7.58 (m, 2H), 7.49-7.53 (m, 3H), 7.40-7.47 (m,5H), 6.79 (s, 1H), 4.54 (br. s., 2H), 4.24 (s, 1H), 4.27 (s, 1H), 3.28(dd, J=13.1, 4.3 Hz, 2H), 3.01 (dt, J=13.6, 6.9 Hz, 1H), 1.52 (d, J=6.8Hz, 6H), 1.31 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H)⁺.

2-((3S,5R)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 102)

¹H NMR (CHLOROFORM-d) δ 7.54-7.61 (m, 2H), 7.45-7.54 (m, 4H), 7.08 (d,J=3.5 Hz, 1H), 6.78 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.90 (br. s.,2H), 4.30 (s, 1H), 4.34 (s, 1H), 3.32 (dd, J=12.9, 4.4 Hz, 2H), 3.01(quin, J=6.9 Hz, 1H), 1.60 (d, J=7.0 Hz, 6H), 1.31 (d, J=7.0 Hz, 6H).LC-MS: m/z 429.1 (M+H)⁺.

2-(4-(furan-2-carbonyl)piperazin-1-yl)-4-isopropyl-6-phenylnicotinonitrile(Compound 103)

Compound 103 was synthesized using isobutyraldehyde and acetophenone asstarting materials.

¹H NMR (DMSO-d₆) δ 8.02-8.08 (m, 2H), 7.50-7.56 (m, 2H), 7.46-7.50 (m,2H), 7.30 (s, 1H), 7.08 (dd, J=3.4, 0.6 Hz, 1H), 6.53 (dd, J=3.3, 1.8Hz, 1H), 4.05 (br. s., 4H), 3.79-3.85 (m, 4H), 3.40 (dt, J=13.7, 6.8 Hz,1H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 400.8 (M+H)⁺.

2-(4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile(Compound 104)

Compound 104 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.51-7.57 (m, 1H), 7.43-7.51 (m, 1H), 7.23-7.28(m, 1H), 7.03-7.11 (m, 3H), 6.75 (s, 1H), 6.53 (dd, J=3.0, 1.5 Hz, 1H),4.02 (br. s., 4H), 3.89 (s, 3H), 3.74-3.82 (m, 4H), 3.00 (dt, J=13.8,6.9 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 430.9 (M+H)⁺.

2-(4-benzoylpiperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile(Compound 105)

Compound 105 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (DMSO-d₆) δ 7.43-7.50 (m, 6H), 7.25 (dd, J=7.4, 1.6 Hz, 1H),7.07-7.10 (m, 1H), 7.02-7.06 (m, 1H), 6.75 (s, 1H), 3.99 (br. s., 2H),3.87 (s, 3H), 3.78 (br. s., 2H), 3.64 (br. s., 4H), 2.99 (dt, J=13.8,6.9 Hz, 1H), 1.31 (s, 3H), 1.29 (s, 3H). LC-MS: m/z 440.8 (M+H)⁺.

2-(4-(1H-indole-3-carbonyl)piperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile(Compound 106)

Compound 106 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 9.02 (br. s., 1H), 7.73-7.80 (m, 1H), 7.41-7.51(m, 3H), 7.21-7.28 (m, 3H), 7.01-7.11 (m, 2H), 6.75 (s, 1H), 3.94 (br.s., 4H), 3.87 (s, 3H), 3.75 (br. s., 4H), 3.02 (dt, J=13.7, 6.8 Hz, 1H),1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 480 (M+H)⁺.

2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 107)

¹H NMR (CHLOROFORM-d) δ 7.55-7.60 (m, 2H), 7.48-7.54 (m, 4H), 7.06 (dd,J=3.5, 0.8 Hz, 1H), 6.77 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.91(br. s., 1H), 4.52 (d, J=13.6 Hz, 1H), 4.29-4.36 (m, 1H), 4.23 (dt,J=13.1, 2.1 Hz, 1H), 3.62 (br. s., 1H), 3.43 (dd, J=13.1, 3.8 Hz, 1H),3.26 (td, J=12.4, 3.5 Hz, 1H), 3.00 (quin, J=6.9 Hz, 1H), 1.50 (d, J=6.8Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H)⁺.

2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-4-isopropyl-6-phenylnicotinonitrile(Compound 108)

Compound 108 was synthesized using benzaldehyde and 3-methylbutan-2-oneas starting materials.

¹H NMR (CHLOROFORM-d) δ 8.00-8.08 (m, 2H), 7.50-7.57 (m, 2H), 7.45-7.50(m, 2H), 7.29 (s, 1H), 7.07 (dd, J=3.5, 0.5 Hz, 1H), 6.52 (dd, J=3.5,1.8 Hz, 1H), 4.94 (br. s., 1H), 4.54 (d, J=13.3 Hz, 1H), 4.34 (dd,J=12.5, 2.3 Hz, 1H), 4.24 (dt, J=13.1, 2.1 Hz, 1H), 3.65 (br. s., 1H),3.41-3.46 (m, 1H), 3.38-3.41 (m, 1H), 3.25 (td, J=12.4, 3.3 Hz, 1H),1.53 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H)⁺.

2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 110)

¹H NMR (CHLOROFORM-d) δ 8.00-8.06 (m, 2H), 7.77 (s, 1H), 7.50 (br. s.,1H), 7.48 (d, J=4.3 Hz, 3H), 7.30 (s, 1H), 6.61 (s, 1H), 4.78 (br. s.,1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.58 (br. s.,1H), 3.40 (quin, J=6.9 Hz, 1H), 3.33 (dd, J=12.9, 3.1 Hz, 1H), 3.17 (td,J=12.4, 3.3 Hz, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 6H).LC-MS: m/z 415.0 (M+H)⁺.

2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-isopropyl-6-phenylnicotinonitrile(Compound III)

Compound III was synthesized using benzaldehyde and 3-methylbutan-2-oneas starting materials.

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.53-7.61 (m, 2H), 7.49-7.53 (m,3H), 7.47 (s, 1H), 6.79 (s, 4H), 6.61 (s, 1H), 4.71-4.76 (br. s., 1H),4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H),3.34 (dd, J=13.1, 3.3 Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt,J=13.7, 6.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.29 (d, J=7.3 Hz, 6H).LC-MS: m/z 414.9 (M+H)⁺.

2-(4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile(Compound 113)

Compound 113 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.42-7.53 (m, 2H), 7.25 (dd,J=7.5, 1.5 Hz, 1H), 7.02-7.13 (m, 2H), 6.76 (s, 1H), 6.59-6.66 (m, 1H),3.90 (br. s., 4H), 3.88 (s, 3H), 3.73 (br. s., 4H), 3.00 (dt, J=13.7,6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 431.0 (M+H)⁺.

4-(3-fluorophenyl)-2-(4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropylnicotinonitrile(Compound 114)

Compound 114 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.42-7.56 (m, 2H), 7.36 (dq, J=7.7, 0.9 Hz, 1H),7.17-7.27 (m, 2H), 7.09 (dd, J=3.4, 0.9 Hz, 1H), 6.76 (s, 1H), 6.53 (dd,J=3.5, 1.8 Hz, 1H), 4.03 (br. s., 4H), 3.83 (dd, J=6.3, 4.0 Hz, 4H),2.95-3.10 (m, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 419.1 (M+H)⁺.

4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropylnicotinonitrile(Compound 115)

Compound 115 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.77-7.80 (m, 1H), 7.45-7.53 (m, 2H), 7.36 (dt,J=7.7, 1.2 Hz, 1H), 7.17-7.28 (m, 2H), 6.77 (s, 1H), 6.62 (dd, J=1.9,0.6 Hz, 1H), 3.92 (br. s., 4H), 3.77 (br. s., 4H), 2.92-3.10 (m, 1H),1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 419.0 (M+H)⁺.

2-(4-(1H-indole-3-carbonyl)piperazin-1-yl)-4-(3-fluorophenyl)-6-isopropylnicotinonitrile(Compound 116)

Compound 116 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.75 (d, J=7.0 Hz, 1H), 7.40-7.63 (m, 3H), 7.36(d, J=7.8 Hz, 1H), 7.17-7.28 (m, 3H), 6.77 (s, 1H), 3.94 (br. s., 4H),3.79 (br. s., 4H), 3.67 (s, 1H), 3.02-3.13 (m, 1H), 1.32 (d, J=6.8 Hz,6H). LC-MS: m/z 468.1 (M+H)⁺.

6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-4-phenylnicotinonitrile(Compound 121)

¹H NMR (CHLOROFORM-d) δ 7.48-7.58 (m, 5H), 7.33-7.39 (m, 3H), 7.30 (d,J=1.5 Hz, 1H), 7.25-7.28 (m, 1H), 6.75 (s, 1H), 4.71 (s, 1H), 4.27 (br.s., 1H), 4.09-4.20 (m, 2H), 3.80 (br. s., 2H), 3.52 (s, 1H), 3.19-3.26(s, 1H), 3.06-3.15 (m, 1H), 2.98 (dt, J=13.7, 6.8 Hz, 1H), 1.40 (s, 3H),1.30 (d, J=4.5 Hz, 19H). LC-MS: m/z 439.2 (M+H)⁺.

4-(3-fluorophenyl)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 127)

Compound 127 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.44-7.58 (m, 2H), 7.31-7.40 (m, 1H), 7.14-7.27(m, 2H), 7.07 (d, J=3.5 Hz, 1H), 6.74 (s, 1H), 6.53 (dd, J=3.5, 1.8 Hz,1H), 4.92 (br. s., 1H), 4.52 (d, J=13.6 Hz, 1H), 4.34 (d, J=10.5 Hz,1H), 4.24 (dt, J=13.1, 2.1 Hz, 1H), 3.62 (br. s., 1H), 3.45 (dd, J=13.3,3.8 Hz, 1H), 3.28 (td, J=12.4, 3.4 Hz, 1H), 3.01 (dt, J=13.6, 6.9 Hz,1H), 1.44-1.54 (m, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 433.0 (M+H)⁺.

4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 128)

Compound 128 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.73-7.81 (m, 1H), 7.44-7.56 (m, 2H), 7.35 (dt,J=8.0, 1.1 Hz, 1H), 7.12-7.27 (m, 2H), 6.75 (s, 1H), 6.61 (dd, J=1.8,0.8 Hz, 1H), 4.77 (br. s., 1H), 4.31 (d, J=12.0 Hz, 2H), 4.23 (d, J=13.1Hz, 1H), 3.57 (br. s., 1H), 3.36 (d, J=10.0 Hz, 1H), 3.19 (td, J=12.4,3.5 Hz, 1H), 3.01 (dt, J=13.5, 6.9 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.31(d, J=6.8 Hz, 6H). LC-MS: m/z 433.1 (M+H)⁺.

2-(4-(1H-indole-3-carbonyl)-3-methylpiperazin-1-yl)-4-(3-fluorophenyl)-6-isopropylnicotinonitrile(Compound 129)

Compound 129 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 8.85 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.40-7.54(m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.15-7.28 (m, 4H), 6.74 (s, 1H), 4.84(br. s., 1H), 4.28 (t, J=15.3 Hz, 3H), 3.59 (d, J=11.8 Hz, 1H), 3.41 (d,J=11.0 Hz, 1H), 3.21 (t, J=10.8 Hz, 1H), 3.00 (dt, J=13.8, 6.9 Hz, 1H),1.45 (d, J=6.5 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 482.2 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 130)

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.55-7.58 (m, 2H), 7.50-7.53 (m,3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.60-6.62 (m, 1H), 4.76 (br.s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.56 (br.s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.5 Hz, 1H),3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz,6H). LC-MS: m/z 415.1 (M+H)⁺.

(R)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-4-phenylnicotinonitrile(Compound 131)

¹H NMR (CHLOROFORM-d) δ 7.52-7.57 (m, 2H), 7.47-7.52 (m, 3H), 7.29-7.41(m, 4H), 7.24-7.28 (m, 1H), 6.75 (s, 1H), 4.98 (br. s., 0.5H), 4.62 (d,J=13.3 Hz, 0.5H), 4.28 (d, J=13.1 Hz, 1H), 4.06-4.20 (m, 2H), 3.81 (br.s., 2H), 3.70-3.79 (m, 0.5H), 3.54 (t, J=11.3 Hz, 0.5H), 3.18-3.33 (m,1H), 3.03-3.17 (m, 1H), 2.99 (dt, J=13.8, 6.9 Hz, 1H), 1.33 (br. s.,3H), 1.29 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H)⁺.

(S)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 132)

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.54-7.59 (m, 2H), 7.49-7.54 (m,3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.59-6.63 (m, 1H), 4.76 (br.s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.3 Hz, 1H), 3.57 (br.s., 1H), 3.34 (dd, J=13.2, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H),3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz,6H). LC-MS: m/z 415.1 (M+H)⁺.

(S)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-4-phenylnicotinonitrile(Compound 133)

¹H NMR (CHLOROFORM-d) δ 7.53-7.56 (m, 2H), 7.47-7.53 (m, 3H), 7.33-7.39(m, 2H), 7.29-7.33 (m, 2H), 7.24-7.28 (m, 1H), 6.75 (s, 1H), 4.98 (br.s., 0.5H), 4.62 (d, J=13.3 Hz, 0.5H), 4.28 (d, J=12.8 Hz, 1H), 4.08-4.20(m, 2H), 3.81 (br. s., 2H), 3.70-3.79 (m, 0.5H), 3.54 (t, J=11.3 Hz,0.5H), 3.17-3.32 (m, 1H), 3.10 (t, J=12.7 Hz, 1H), 2.98 (dt, J=13.7, 6.8Hz, 1H), 1.31-1.35 (m, 3H), 1.29 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1(M+H)⁺.

4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 134)

Compound 134 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (DMSO-d₆) δ 7.77 (s, 1H), 7.45-7.53 (m, 2H), 7.35 (d, J=8.3 Hz,1H), 7.17-7.25 (m, 2H), 6.76 (s, 1H), 6.65 (d, J=1.0 Hz, 1H), 4.71 (br.s., 1H), 4.31 (d, J=12.8 Hz, 2H), 3.50-3.69 (m, 1H), 3.27 (dd, J=13.2,4.4 Hz, 2H), 3.01 (quin, J=7.0 Hz, 1H), 1.56 (d, J=7.0 Hz, 6H), 1.32 (s,3H), 1.30 (s, 3H). LC-MS: m/z 447.1 (M+H)⁺.

2-(3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl)-4-(3-fluorophenyl)-6-isopropylnicotinonitrile(Compound 135)

Compound 135 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.43-7.55 (m, 1H), 7.12-7.40 (m, 8H), 6.74 (s,1H), 4.90 (br. s., 1H), 4.26 (br. s., 3H), 3.82 (s, 2H), 3.14 (br. s.,2H), 3.00 (dt, J=13.8, 6.9 Hz, 1H), 1.44 (d, J=6.8 Hz, 6H), 1.30 (d,J=6.8 Hz, 6H). LC-MS: m/z 471.1 (M+H)⁺.

4-(3-fluorophenyl)-2-(4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 136)

Compound 136 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.45-7.55 (m, 2H), 7.32-7.38 (m, 1H), 7.15-7.28(m, 2H), 7.08 (d, J=3.5 Hz, 1H), 6.74 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz,1H), 4.90 (br. s., 2H), 4.34 (d, J=13.1 Hz, 2H), 3.33 (dd, J=13.1, 4.5Hz, 2H), 2.93-3.08 (m, 1H), 1.59 (d, J=7.0 Hz, 6H), 1.31 (d, J=6.8 Hz,6H). LC-MS: m/z 447.0 (M+H)⁺.

6-cyclohexyl-2-(4-(furan-2-carbonyl)piperazin-1-yl)-4-phenylnicotinonitrile(Compound 137)

Compound 137 was synthesized using benzaldehyde and 1-cyclohexylethanoneas starting materials.

¹H NMR (CHLOROFORM-d) δ 7.46-7.61 (m, 6H), 7.08 (dd, J=3.4, 0.9 Hz, 1H),6.78 (s, 1H), 6.53 (dd, J=3.4, 1.9 Hz, 1H), 4.03 (br. s., 4H), 3.76-3.86(m, 4H), 2.66 (tt, J=11.6, 3.3 Hz, 1H), 1.92-2.00 (m, 2H), 1.83-1.91 (m,2H), 1.74-1.82 (m, 1H), 1.55 (qd, J=12.3, 2.8 Hz, 2H), 1.41 (qt, J=12.6,3.1 Hz, 2H), 1.25-1.35 (m, 1H). LC-MS: m/z 441.0 (M+H)⁺.

6-cyclohexyl-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-phenylnicotinonitrile(Compound 138)

Compound 138 was synthesized using benzaldehyde and 1-cyclohexylethanoneas starting materials.

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.43-7.61 (m, 6H), 6.77 (s, 1H),6.61 (s, 1H), 4.76 (br. s., 1H), 4.29 (d, J=12.3 Hz, 2H), 4.20 (d,J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.33 (dd, J=13.2, 3.1 Hz, 1H), 3.16(td, J=12.5, 3.1 Hz, 1H), 2.56-2.72 (m, 1H), 1.95 (d, J=12.5 Hz, 2H),1.87 (d, J=12.8 Hz, 2H), 1.78 (d, J=12.8 Hz, 1H), 1.49-1.60 (m, 2H),1.46 (d, J=6.5 Hz, 3H), 1.35-1.44 (m, 2H), 1.25-1.34 (m, 1H). LC-MS: m/z455.1 (M+H)⁺.

6-cyclohexyl-2-((3S,5R)-4-(furan-3-carbonyl)-3,5-dimethylpiperazin-1-yl)-4-phenylnicotinonitrile(Compound 142)

Compound 142 was synthesized using benzaldehyde and 1-cyclohexylethanoneas starting materials.

¹H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.54-7.58 (m, 2H), 7.49-7.53 (m,3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.65 (d, J=2.0 Hz, 1H), 4.73(br. s., 2H), 4.27 (d, J=13.1 Hz, 2H), 3.25 (dd, J=13.1, 4.5 Hz, 2H),2.66 (tt, J=11.6, 3.4 Hz, 1H), 1.95 (d, J=12.5 Hz, 2H), 1.84-1.92 (m,2H), 1.78 (d, J=12.5 Hz, 1H), 1.57 (d, J=7.0 Hz, 6H), 1.49-1.54 (m, 2H),1.38-1.47 (m, 2H), 1.31-1.37 (m, 1H). LC-MS: m/z 469.1 (M+H)⁺.

6-isopropyl-4-(2-methoxyphenyl)-2-(4-(2-phenylacetyl)piperazin-1-yl)nicotinonitrile(Compound 146)

Compound 146 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.42-7.48 (m, 1H), 7.28-7.40 (m, 5H), 7.23 (dd,J=7.5, 1.8 Hz, 1H), 7.01-7.10 (m, 2H), 6.73 (s, 1H), 3.83-3.90 (m, 5H),3.82 (s, 2H), 3.62-3.70 (m, 4H), 3.49-3.56 (m, 2H), 2.91-3.03 (m, 1H),1.29 (d, J=6.8 Hz, 6H). LC-MS: m/z 455.2 (M+H)⁺.

2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile(Compound 147)

Compound 147 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.52 (dd, J=1.8, 0.8 Hz, 1H), 7.41-7.48 (m, 1H),7.25 (dd, J=7.5, 1.8 Hz, 1H), 7.00-7.16 (m, 3H), 6.73 (s, 1H), 6.52 (dd,J=3.5, 1.8 Hz, 1H), 4.91 (br. s., 1H), 4.51 (d, J=12.3 Hz, 1H), 4.32 (d,J=12.5 Hz, 1H), 4.22 (dt, J=13.2, 2.0 Hz, 1H), 3.88 (s, 3H), 3.62 (br.s., 1H), 3.39 (dd, J=13.2, 3.6 Hz, 1H), 3.22 (td, J=12.4, 3.5 Hz, 1H),3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.49 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8Hz, 6H). LC-MS: m/z 455.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile(Compound 148)

Compound 148 was synthesized using 2-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.76 (dd, J=1.5, 0.8 Hz, 1H), 7.40-7.51 (m, 2H),7.22-7.28 (m, 1H), 7.01-7.11 (m, 2H), 6.70-6.76 (m, 1H), 6.61 (dd,J=1.8, 0.8 Hz, 1H), 4.75 (br. s., 1H), 4.16-4.45 (m, 3H), 3.88 (s, 3H),3.55 (br. s., 1H), 3.31 (dd, J=12.9, 3.4 Hz, 1H), 3.14 (td, J=12.5, 3.4Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.30 (d,J=6.8 Hz, 6H). LC-MS: m/z 445.2 (M+H)⁺.

6-isopropyl-4-(2-methoxyphenyl)-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)nicotinonitrile(Compound 149)

Compound 149 was synthesized using 3-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.41-7.49 (m, 1H), 7.29-7.40 (m, 4H), 7.20-7.28(m, 2H), 7.01-7.09 (m, 2H), 6.71 (s, 1H), 4.97 (br. s., 1H), 4.60 (d,J=13.3 Hz, 1H), 4.25 (br. s., 1H), 4.16 (d, J=13.3 Hz, 1H), 3.87 (s,3H), 3.64-3.81 (m, 2H), 3.53 (t, J=11.4 Hz, 1H), 3.14-3.29 (m, 1H),2.85-3.14 (m, 2H), 1.62 (s, 3H), 1.29 (s, 6H). LC-MS: m/z 469.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-(3-methoxyphenyl)nicotinonitrile(Compound 151)

Compound 151 was synthesized using 3-methoxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.76 (dd, J=1.5, 0.8 Hz, 1H), 7.38-7.50 (m, 2H),7.00-7.17 (m, 3H), 6.76-6.81 (m, 1H), 6.61 (dd, J=1.9, 0.9 Hz, 1H), 4.76(br. s., 1H), 4.29 (d, J=12.8 Hz, 2H), 4.21 (d, J=13.1 Hz, 1H),3.84-3.92 (m, 3H), 3.56 (br. s., 1H), 3.33 (dd, J=13.2, 3.6 Hz, 1H),3.17 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.47 (d,J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H). LC-MS: m/z 445.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(3-hydroxyphenyl)-6-isopropylnicotinonitrile(Compound 152)

Compound 152 was synthesized using 3-hydroxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.74-7.81 (m, 1H), 7.41-7.51 (m, 1H), 7.34 (t,J=7.9 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.97 (dd, J=8.2,2.4 Hz, 1H), 6.79 (s, 1H), 6.57-6.64 (m, 1H), 4.79 (br. s., 1H),4.15-4.44 (m, 3H), 3.59 (br. s., 1H), 3.34 (d, J=10.5 Hz, 1H), 3.17 (td,J=12.5, 3.1 Hz, 1H), 2.93-3.04 (m, 1H), 1.47 (d, J=6.8 Hz, 3H),1.27-1.31 (m, 6H). LC-MS: m/z 431.2 (M+H)⁺.

2-(4-(furan-3-carbonyl)-3-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 154)

¹H NMR (CHLOROFORM-d) δ 7.61 (br. s., 1H), 7.50-7.54 (m, 2H), 7.46-7.50(m, 3H), 7.37-7.43 (m, 3H), 7.34 (t, J=7.7 Hz, 2H), 7.22-7.27 (m, 1H),6.67 (s, 1H), 6.52 (br. s., 1H), 5.75 (br. s., 1H), 4.57 (br. s., 2H),4.29 (d, J=11.5 Hz, 1H), 4.00 (d, J=11.0 Hz, 1H), 3.60-3.74 (m, 1H),3.55 (d, J=10.5 Hz, 1H), 2.94 (dt, J=13.6, 6.8 Hz, 1H), 1.25-1.27 (m,3H), 1.23 (d, J=7.0 Hz, 3H). LC-MS: m/z 477.1 (M+H)⁺.

2-(4-(furan-2-carbonyl)-3-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 155)

¹H NMR (CHLOROFORM-d) δ 7.51-7.55 (m, 2H), 7.46-7.50 (m, 4H), 7.45 (d,J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.20-7.25 (m, 1H), 6.92-7.07 (m,1H), 6.68 (s, 1H), 6.45 (br. s., 4H), 5.95 (t, J=4.5 Hz, 1H), 4.63 (s,1H), 4.66 (s, 1H), 4.33 (d, J=11.0 Hz, 1H), 4.06 (dd, J=13.6, 4.0 Hz,1H), 3.69 (br. s., 1H), 3.56-3.65 (m, 1H), 2.97 (dt, J=13.7, 6.8 Hz,1H), 1.24-1.28 (m, 6H). LC-MS: m/z 477.1 (M+H)⁺.

(R)-4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 156)

Compound 156 was synthesized using 3-fluorobenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.77 (dd, J=1.5, 1.0 Hz, 1H), 7.43-7.53 (m, 2H),7.35 (dq, J=7.7, 0.9 Hz, 1H), 7.12-7.28 (m, 2H), 6.67-6.80 (m, 1H), 6.61(dd, J=1.9, 0.9 Hz, 1H), 4.76 (br. s., 1H), 4.17-4.45 (m, 3H), 3.56 (br.s., 1H), 3.36 (dd, J=13.1, 3.5 Hz, 1H), 3.18 (td, J=12.5, 3.5 Hz, 1H),2.95-3.07 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.29-1.32 (m, 6H). LC-MS: m/z433.1 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-isopropylnicotinonitrile(Compound 157)

Compound 157 was synthesized using 2-hydroxybenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 8.01 (dd, J=8.2, 1.4 Hz, 1H), 7.73-7.77 (m, 1H),7.50-7.60 (m, 1H), 7.46 (t, J=1.6 Hz, 1H), 7.31-7.37 (m, 2H), 7.21 (s,1H), 6.60 (dd, J=1.6, 0.6 Hz, 1H), 4.71 (br. s., 1H), 4.25 (br. s., 1H),4.07 (d, J=13.3 Hz, 1H), 3.98 (d, J=13.8 Hz, 1H), 3.71 (br. s., 1H),3.45-3.56 (m, 1H), 3.15-3.26 (m, 1H), 3.06 (dt, J=13.7, 6.8 Hz, 1H),1.32-1.37 (m, 9H). LC-MS: m/z 432.2 (M+H)⁺.

(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-o-tolylnicotinonitrile(Compound 158)

Compound 158 was synthesized using 2-methylbenzaldehyde and3-methylbutan-2-one as starting materials.

¹H NMR (CHLOROFORM-d) δ 7.72-7.79 (m, 1H), 7.47 (t, J=1.6 Hz, 1H),7.29-7.40 (m, 3H), 7.19 (d, J=6.8 Hz, 1H), 6.65 (s, 1H), 6.60 (dd,J=1.9, 0.9 Hz, 1H), 4.75 (br. s., 1H), 4.17-4.46 (m, 3H), 3.42-3.67 (m,1H), 3.34 (dd, J=13.1, 3.5 Hz, 1H), 3.16 (td, J=12.5, 3.5 Hz, 1H),2.92-3.03 (m, 1H), 2.24 (s, 3H), 1.45 (d, J=6.3 Hz, 3H), 1.30 (d, J=6.8Hz, 6H). LC-MS: m/z 429.1 (M+H)⁺.

2-(4-(furan-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 160)

¹H NMR (CHLOROFORM-d) δ 7.69 (br. s., 1H), 7.64 (s, 1H), 7.45 (br. s.,2H), 7.36-7.44 (m, 4H), 7.31 (br. s., 2H), 7.16-7.26 (m, 3H), 6.57 (br.s., 1H), 5.37 (br. s., 1H), 4.15 (d, J=9.8 Hz, 2H), 3.96 (d, J=8.8 Hz,4H), 2.98-3.12 (m, 1H), 1.13 (d, J=6.8 Hz, 6H). LC-MS: m/z 477.2 (M+H)⁺.

(R)-2-(3-cyano-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropylpyridin-4-yl)phenylacetate (Compound 162)

Compound 162 was synthesized from(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-isopropylnicotinonitrile(Compound 157) by reaction with acetyl chloride.

¹H NMR (METHANOL-d₄) δ 7.76 (s, 1H), 7.39-7.58 (m, 3H), 7.31 (t, J=1.9Hz, 1H), 7.24 (dd, J=7.7, 1.9 Hz, 1H), 6.78 (s, 1H), 6.61 (d, J=1.3 Hz,1H), 4.76 (br. s., 1H), 4.17-4.44 (m, 3H), 3.56 (br. s., 1H), 3.34 (dd,J=12.9, 3.4 Hz, 1H), 3.17 (td, J=12.5, 3.5 Hz, 1H), 2.93-3.06 (m, 1H),2.27-2.43 (m, 3H), 1.46 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H).LC-MS: m/z 473.1 (M+H)⁺.

(R)-4-(2-ethoxyphenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropylnicotinonitrile(Compound 163)

Compound 163 was synthesized from(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-isopropylnicotinonitrile(Compound 157) by treatment with NaH/DMF followed by ethyl bromidequench.

¹H NMR (METHANOL-d₄) δ 7.76 (s, 1H), 7.37-7.51 (m, 2H), 6.98-7.16 (m,3H), 6.79 (s, 1H), 6.57-6.64 (m, 1H), 4.76 (br. s., 1H), 4.17-4.45 (m,3H), 4.12 (q, J=7.0 Hz, 2H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6Hz, 1H), 3.17 (td, J=12.4, 3.3 Hz, 1H), 3.00 (quin, J=6.9 Hz, 1H), 1.47(dt, J=6.8, 3.5 Hz, 6H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 459.1(M+H)⁺.

2-(4-(furan-2-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 167)

¹H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.52 (s, 1H), 7.36-7.48 (m, 5H),7.31 (br. s., 2H), 7.22 (d, J=6.5 Hz, 3H), 7.07 (d, J=3.0 Hz, 1H), 6.52(br. s., 1H), 5.37-5.59 (br. s., 1H), 4.17 (br. s., 3H), 3.98 (br. s.,2H), 3.92 (br. s., 1H), 3.00-3.12 (m, 1H), 1.13 (d, J=6.5 Hz, 3H), 0.79(br. s., 3H). LC-MS: m/z 477.1 (M+H)⁺.

2-(4-(1H-indole-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile(Compound 169)

¹H NMR (CHLOROFORM-d) δ 9.00 (br. s., 1H), 7.71 (d, J=6.3 Hz, 1H), 7.64(s, 1H), 7.42 (d, J=7.3 Hz, 6H), 7.24-7.34 (m, 4H), 7.22 (d, J=6.3 Hz,4H), 5.53 (br. s., 1H), 4.13-4.35 (m, 2H), 4.01 (br. s., 2H), 3.76-3.96(m, 2H), 3.00-3.13 (m, 1H), 1.14 (d, J=6.5 Hz, 3H), 0.80 (d, J=6.5 Hz,3H). LC-MS: m/z 526.1 (M+H)⁺.

Example 11 Preparation of (R)-methyl5-(4-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinate(Compound 244)

Compound 244 was prepared according to Scheme 8.

Step 1:(R)-5-bromo-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinonitrile(58)

To a solution of(R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (6;Example 1; 1 g, 3.10 mmol) and triethylamine (375 mg, 3.72 mmol) in 20mL THF was added 1-(chloromethyl)-4-methoxybenzene (485 mg, 3.10 mmol)dropwise at 0° C. The reaction mixture was stirred at 0° C. for 4 hrsbefore warmed up to room temperature and quenched by adding 20 mL ofwater. Solvent was removed under reduced pressure and the residue wasextracted with EtOAc (3×20 mL). The combined organic layer was thenwashed with brine, dried over anhy. Na₂SO₄ and concentrated in vacuo.Flash column chromatography separation (20% EtOAc/petroleum ether) thenafforded 1.3 g of 58 as thick brown oil. MS (ES) M+H expected 443.1,found 443.2

Step 2:(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinonitrile(59)

To a solution of(R)-5-bromo-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)-nicotinonitrile(58; 1 g, 2.18 mmol) and 4-fluorophenylboronic acid (610 mg, 4.36 mmol)in 5 mL of DMF was added Pd(PPh₃)₄ (340 mg 0.218 mmol) and K₂CO₃ (360mg, 2.62 mmol) under nitrogen protection. The reaction was subjected tomicrowave reaction at 150° C. for 1 hour. After dilution with 20 mL ofwater, the mixture was extracted with EtOAc (3×20 mL). The combinedorganic layer was washed with brine, dried over anhy. Na₂SO₄ andconcentrated in vacuo. Flash column chromatography separation (20%EtOAc/petroleum ether) then afforded 600 mg of 59 as thick brown oil. MS(ES) M+H expected 459.3, found 459.2.

Step 3:(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinicacid (60)

To a solution of(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methyl-piperazin-1-yl)nicotinonitrile(600 mg, 1.31 mmol) in 20 mL of ethanol was added 20 mL 50% aq. NaOHsolution. The reaction mixture was heated to 120° C. overnight, and thenacidified with 2N aq. HCl to pH<6. Ethanol was removed under reducedpressure and the residue was washed with water several times andfiltered. After air-drying, 500 mg of crude title compound was obtainedas a yellowish solid. MS (ES) M+H expected 478.2, found 478.2.

Step 4:(R)-methyl-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinate(61)

To a 25 mL of round-bottom flask was charged with 10 mL of methanol.After cooling at 0° C., 1 mL of thionyl chloride was added dropwise andthe solution was stirred at room temperature for 30 min, before adding(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxy-benzyl)-3-methylpiperazin-1-yl)nicotinicacid (500 mg, 1.05 mmol) slowly. The resulting mixture was then heatedto reflux temperature for 2 hrs. After removing the volatile underreduced pressure, 500 mg of crude title compound was obtained and usedwithout further purification. MS (ES) M+H expected 492.3, found 492.2.

Step 5: (R)-methyl5-(4-fluorophenyl)-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinate (62)

(R)-methyl-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinate(61; 500 mg, 1.02 mmol) was dissolved in 15 mL of 2,2,2-trifluoroaceticacid. The mixture was heated to reflux overnight. After removal ofexcess of TFA under reduced pressure, the residue was re-dissolved inmethylene chloride and washed with satd. NaHCO₃, brine. The organiclayer was then dried over anhy. Na₂SO₄, and concentrated in vacuo. 300mg of title compound was obtained as yellowish oil and used subsequentlywithout further purification. MS (ES) M+H expected 372.2, found 372.2.

Step 6: (R)-methyl5-(4-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinate(Compound 244)

¹H NMR (CHLOROFORM-d) δ 7.84 (s, 1H), 7.20-7.25 (m, 2H), 7.06-7.15 (m,2H), 4.86 (br. s., 0.5H), 4.43 (d, J=12.5 Hz, 0.5H), 4.21 (d, J=6.0 Hz,0.5H), 3.92 (d, J=13.1 Hz, 0.5H), 3.87 (s, 3H), 3.81 (d, J=16.3 Hz, 1H),3.74 (t, J=6.7 Hz, 3H), 3.64 (br. s., 1H), 3.37 (s, 3H), 3.18-3.34 (m,1H), 2.96-3.15 (m, 2H), 2.64-2.80 (m, 1H), 2.60 (br. s., 1H), 1.34-1.40(m, 1.5H), 1.29-1.32 (m, 1.5H), 1.17 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.5Hz, 3H). LC-MS: m/z 458.2 (M+H)⁺.

Example 12 Assays for IDH1 R132H Inhibitors

Assays were conducted in a volume of 76 μl assay buffer (150 mM NaCl, 10mM MgCl₂, 20 mM Tris pH 7.5, 0.03% bovine serum albumin) as follows in astandard 384-well plate: To 25 ul of substrate mix (8 uM NADPH, 2 mMaKG), 1 μl of test compound was added in DMSO. The plate was centrifugedbriefly, and then 25 μl of enzyme mix was added (0.2 μg/ml IDH1 R132H)followed by a brief centrifugation and shake at 100 RPM. The reactionwas incubated for 50 minutes at room temperature, then 25 μl ofdetection mix (30 μM resazurin, 36 μg/ml) was added and the mixturefurther incubated for 5 minutes at room temperature. The conversion ofresazurin to resorufin was detected by fluorescent spectroscopy at Ex544Em590 c/o 590.

Certain of the compounds of Formula I set forth in Tables 1 and 5 weretested in this assay and the results set forth below in Table 3. As usedin Table 3, “A” refers to an inhibitory activity against IDH1 R132H withan IC₅₀≦1.0 μM; “B” refers to an inhibitory activity against IDH1 R132Hwith an IC₅₀ greater than 1 μM and ≦5 μM; “C” refers to an inhibitoryactivity against IDH1 R132H with an IC₅₀ greater than 5 μM and ≦15 μM.

TABLE 3 IDH1 R132H Inhibition by Compounds of Formula I. Cmpd No. IC₅₀100 C 101 B 102 B 103 C 104 C 105 B 106 C 107 B 108 C 109 C 110 B 111 C113 C 114 B 115 B 116 C 117 C 118 C 119 C 120 B 121 C 122 C 123 C 124 C125 C 126 B 127 C 128 B 129 C 130 B 131 B 132 B 133 B 134 B 135 B 136 C137 C 138 B 139 B 140 B 141 C 142 B 143 B 144 B 145 B 146 C 147 C 148 B149 B 150 B 151 B 152 B 153 C 154 C 155 C 156 B 157 C 158 B 159 C 160 C161 B 162 B 163 B 164 B 165 B 166 C 167 B 168 B 169 B 170 B 171 B 172 C173 B 174 B 175 B 176 B 177 B 178 B 179 B 180 B 181 B 182 A 183 B 184 B185 B 187 A 188 B 189 B 190 C 191 A 192 B 193 B 195 B 196 B 197 B 198 B199 B 200 B 201 B 202 B 203 B 204 B 205 B 206 B 207 A 208 B 209 B 210 C211 B 212 A 213 B 214 B 215 B 216 B 217 B 218 B 219 A 220 B 221 B 222 A223 A 224 A 225 A 226 A 227 A 228 B 229 A 230 B 231 B 232 B 233 B 234 A235 A 236 A 237 B 238 B 239 B 240 B 241 A 242 A 243 A 244 B 245 B 246 A247 B 248 A 249 A 250 A 251 A 252 A 253 A 254 B 255 A 256 A 257 A 258 A259 A 260 A 261 A 262 A

Certain of the compounds of Formula I set forth in Table 5 were testedin this assay and the assay in Example 13 and the results set forthbelow in Table 4. As used in Table 4, “A1” refers to an inhibitoryactivity against IDH1 R132H with an IC₅₀≦0.5 μM or an IC₅₀ forinhibition of 2-HG production ≦0.5 μM; “B1” refers to an inhibitoryactivity against IDH1 R132H with an IC₅₀ greater than 0.5 μM and ≦1 μMor an IC₅₀ for inhibition of 2-HG production greater than 0.5 μM and ≦1μM; “C1” refers to an inhibitory activity against IDH1 R132H with anIC₅₀ greater than 1 μM and ≦10 μM or an IC₅₀ for inhibition of 2-HGproduction greater than 1 μM and ≦10 μM; and “D1” refers to aninhibitory activity against IDH1 R132H with an IC₅₀ greater than 10 μMor an IC₅₀ for inhibition of 2-HG production greater than 10 μM.

TABLE 4 IDH1R 132H HT1080 Cmpd IC50 IC50 U87R132H No. (μM) (μM) IC50(μM) 263 A1 B1 C1 264 B1 C1 C1 265 A1 C1 C1 266 A1 C1 C1 267 B1 C1 C1268 B1 C1 C1 269 A1 C1 C1 270 B1 C1 C1 271 A1 C1 C1 272 B1 C1 C1 273 B1274 B1 C1 C1 275 A1 C1 C1 276 A1 C1 C1 277 A1 C1 C1 278 B1 C1 C1 279 B1C1 C1 280 A1 C1 C1 281 B1 282 B1 283 A1 B1 C1 284 B1 285 A1 B1 C1 286 A1A1 A1 287 A1 C1 C1 288 A1 A1 A1 289 A1 290 A1 291 B1 292 A1 B1 C1 293 A1C1 C1 294 A1 B1 B1 295 A1 B1 B1 296 A1 B1 B1 297 A1 B1 C1 298 B1 299 A1B1 B1 300 B1 301 A1 C1 C1 302 A1 C1 C1 303 A1 C1 C1 304 A1 C1 B1 305 B1306 B1 307 A1 C1 C1 308 A1 C1 C1 309 A1 B1 B1 310 B1 311 B1 312 A1 B1 C1313 A1 C1 B1 314 B1 315 A1 A1 B1 316 B1 317 B1 318 A1 319 A1 320 A1 B1A1 321 A1 B1 A1 322 A1 323 A1 B1 B1 324 B1 325 A1 A1 A1 326 A1 B1 A1 327B1 328 A1 329 B1 330 A1 A1 A1 331 A1 332 B1 333 A1 334 B1 335 A1 B1 A1336 B1 337 B1 338 A1 339 B1 340 A1 B1 B1 341 A1 342 A1 A1 A1 343 A1 A1A1 344 B1 345 A1 C1 B1 346 A1 C1 B1 347 A1 A1 A1 348 A1 349 B1 350 A1 C1B1 351 A1 C1 B1 352 A1 C1 B1 353 A1 B1 B1 354 B1 355 B1 356 A1 C1 C1 357B1 358 A1 359 A1 360 A1 C1 C1 361 A1 C1 B1 362 A1 363 A1 C1 B1 364 A1 B1A1 365 366 367 368 B1 369 B1 370 B1 371 B1 372 A1 373 A1 C1 B1 374 A1 C1B1 375 B1 376 A1 C1 B1 377 A1 B1 A1 378 A1 379 B1 380 A1 B1 B1 381 A1 A1A1 382 A1 A1 B1 383 A1 C1 C1 384 A1 B1 B1 385 B1 386 A1 C1 B1 387 A1 A1A1 388 A1 C1 B1 389 A1 A1 A1 390 A1 A1 A1 391 A1 B1 B1 392 A1 393 A1 C1B1 394 B1 395 B1 396 A1 397 A1 398 A1 C1 B1 399 B1 400 B1 C1 C1 401 B1C1 C1 402 A1 403 A1 B1 B1 404 B1 405 A1 406 A1 C1 C1 407 A1 A1 A1 408 A1B1 A1 409 A1 A1 A1 410 A1 A1 A1 411 A1 B1 B1 412 A1 C1 B1 413 B1 414 B1415 A1 C1 C1 416 B1 C1 B1 417 A1 A1 A1 418 A1 A1 A1 419 A1 A1 A1 420 A1C1 C1 421 B1 422 B1 423 B1 424 A1 B1 B1 425 B1 C1 C1 426 B1 C1 C1 427 A1A1 A1 428 A1 A1 B1 429 A1 C1 C1 430 C1 431 B1 B1 B1 432 B1 C1 C1 433 A1A1 A1 434 A1 C1 C1 435 B1 436 A1 B1 B1 437 B1 438 A1 C1 B1 439 A1 A1 440A1 441 B1 442 A1 A1 A1 443 A1 A1 A1 444 A1 A1 A1 445 A1 C1 446 A1 A1 C1447 B1 C1 C1 448 A1 C1 C1 449 B1 C1 C1 450 B1 451 A1 C1 C1 452 A1 C1 C1453 A1 B1 A1 454 A1 A1 A1 455 B1 456 A1 A1 A1 457 A1 B1 B1 458 A1 B1 B1459 A1 A1 A1 460 A1 461 B1 462 B1 C1 C1 463 A1 C1 C1 464 B1 465 B1 466A1 C1 B1 467 B1 468 A1 C1 C1 469 A1 C1 C1 470 A1 C1 C1 471 A1 472 A1 A1A1 473 A1 C1 B1 474 A1 / 475 A1 B1 A1 476 A1 B1 A1 477 B1 478 B1 479 B1480 A1 A1 A1 481 A1 A1 A1 482 A1 483 A1 C1 B1 484 B1 485 A1 A1 A1 486 B1487 A1 488 A1 A1 B1 489 B1 490 B1 491 A1 B1 492 B1 B1 493 B1 494 A1 495B1 496 B1 B1 A1 497 A1 498 A1 A1 A1 499 B1 C1 C1 500 A1 A1 A1 501 B1 502B1 503 A1 504 B1 505 A1 506 B1 507 B1 508 A1 A1 A1 509 B1 510 B1 511 A1B1 512 A1 513 B1 514 A1 A1 515 B1 C1 516 A1 B1 517 A1 B1 518 A1 A1 A1519 B1 520 B1 A1 521 A1 522 B1 C1 523 B1 524 A1 525 A1 526 B1 A1 A1 527A1 A1 A1 528 A1 B1 A1 529 A1 B1 530 A1 A1 A1 531 A1 532 A1 533 B1 C1 534A1 535 A1 A1 536 A1 A1 537 A1 B1 538 A1 539 A1 C1 540 A1 541 A1 A1 A1542 A1 A1 A1 543 B1 544 A1 B1 545 B1 546 A1 A1 A1 547 A1 A1 A1 548 B1549 A1 550 B1 A1 A1 551 A1 A1 A1 552 A1 553 A1 A1 554 A1 555 A1 B1 556A1 557 A1 B1 558 A1 A1 A1 559 A1 C1 560 A1 C1 561 A1 A1 A1 562 A1 A1 A1563 A1 A1 564 A1 565 A1 B1 B1 566 A1 B1 567 B1 568 A1 A1 A1 569 A1 A1570 A1 A1 571 A1 A1 572 A1 A1 573 A1 A1 A1 574 A1 A1 575 A1 A1 576 B1 A1577 A1 A1 578 A1 A1 579 A1 A1 A1 580 A1 A1 A1 581 A1 A1 A1 582 A1 C1 583B1 584 B1 585 A1 A1 A1 586 A1 587 A1 A1 A1 588 A1 A1 589 A1 A1 A1 590 A1A1 A1 591 A1 A1 A1 592 A1 A1 A1 593 B1 594 A1 A1 595 A1 A1 A1 596 A1 A1597 A1 A1 A1 598 A1 B1 599 A1 A1 A1 600 B1 B1 601 A1 602 A1 A1 603 A1 A1A1 604 A1 A1 605 A1 A1 A1 606 A1 A1 607 A1 A1 608 A1 A1 A1 609 A1 A1 A1610 A1 A1 A1 611 A1 A1 A1 612 A1 A1 A1 613 A1 A1 A1 614 A1 615 A1 A1 A1616 A1 617 A1 A1 A1 618 A1 A1 A1 619 A1 A1 620 A1 A1 621 A1 A1 B1 622 B1C1 623 B1 624 A1 A1 625 A1 A1 A1 626 A1 A1 A1 627 A1 A1 A1 628 A1 A1 A1629 A1 A1 A1 630 B1 631 A1 A1 A1 632 A1 633 A1 A1 A1 634 A1 A1 A1 635 A1A1 A1 636 A1 A1 A1 637 A1 A1 A1 638 A1 A1 A1 639 A1 A1 A1 640 A1 641 A1642 A1 A1 A1 643 A1 A1 B1 644 A1 A1 A1 645 A1 A1 A1 646 A1 647 A1 A1 A1648 A1 A1 A1 649 A1 A1 A1 650 A1 A1 651 A1 A1 652 A1 A1 A1 653 A1 A1 654A1 A1 A1 655 A1 A1 656 B1 657 A1 A1 A1 658 A1 A1 659 A1 660 A1 A1 A1 661A1 662 A1 A1 663 A1 A1 A1 664 A1 A1 665 A1 666 A1 A1 A1 667 A1 A1 A1 668A1 B1 669 A1 A1 670 A1 A1 A1 671 A1 672 B1 C1 673 B1 674 A1 A1 A1 675 A1C1 B1 676 A1 A1 A1 677 A1 A1 678 A1 A1 A1 679 A1 A1 680 A1 A1 681 A1 A1A1 682 A1 683 A1 684 A1 A1 685 C1 686 A1 A1 A1 687 A1 B1 688 A1 A1 A1689 A1 A1 A1 690 A1 A1 A1 691 A1 A1 A1 692 A1 A1 A1 693 A1 A1 A1 694 A1B1 A1 695 A1 A1 A1 696 A1 A1 A1 697 A1 A1 A1 698 A1 A1 A1 699 A1 700 A1A1 701 A1 702 A1 C1 C1 703 A1 A1 A1 704 A1 705 A1 A1 A1 706 A1 A1 A1 707A1 A1 A1 708 A1 C1 709 A1 A1 A1 710 A1 A1 A1 711 A1 A1 A1 712 A1 C1 713A1 A1 A1 714 A1 A1 A1 715 A1 A1 A1 716 A1 A1 A1 717 A1 A1 A1 718 A1 B1A1 719 A1 A1 A1 720 A1 A1 A1 721 A1 A1 A1 722 A1 A1 A1 723 A1 724 A1 A1A1 725 A1 A1 A1 726 A1 A1 A1 727 A1 A1 A1 728 A1 A1 A1 729 A1 730 A1 A1A1 731 A1 732 A1 A1 A1 733 A1 B1 A1 734 A1 735 A1 A1 A1 736 A1 A1 A1 737A1 B1 B1 738 A1 A1 A1 739 A1 740 A1 A1 A1 741 A1 A1 A1 742 A1 A1 A1 743A1 A1 A1 744 A1 A1 A1 745 A1 A1 A1 746 A1 A1 A1 747 A1 A1 A1 748 A1 A1A1 749 A1 A1 A1 750 A1 A1 A1 751 A1 A1 A1 752 A1 A1 A1 753 A1 A1 A1 754A1 A1 A1 755 A1 A1 A1 756 A1 A1 A1 757 A1 A1 758 A1 A1 759 A1 A1 760 A1A1 A1 761 A1 A1 A1 762 A1 A1 A1 763 A1 A1 A1 764 A1 A1 A1 765 A1 A1 A1766 A1 A1 A1 767 A1 A1 A1 768 A1 A1 A1 769 A1 A1 A1 770 A1 A1 A1 771 A1A1 A1 772 B1 773 A1 A1 774 A1 A1 A1 775 A1 A1 A1 776 A1 A1 A1 777 A1 A1A1 778 A1 A1 A1 779 C1 780 A1 781 A1 A1 A1 782 A1 A1 A1 783 A1 A1 784 A1A1 A1 785 A1 A1 A1 786 A1 A1 A1 787 A1 A1 A1 788 A1 A1 A1 789 A1 A1 A1790 A1 791 A1 792 A1 C1 C1 793 A1 A1 A1 794 A1 A1 A1 795 A1 796 A1 A1 A1797 A1 A1 A1 798 A1 799 A1 A1 A1 800 A1 A1 A1 801 A1 A1 A1 802 A1 803 A1A1 A1 804 A1 A1 B1 805 A1 A1 A1 806 A1 A1 A1 807 A1 A1 808 A1 A1 809 A1A1 810 B1 A1 A1 811 A1 A1 A1 812 A1 A1 A1 813 A1 A1 A1 814 B1 815 A1 A1816 B1 817 A1 A1 818 A1 A1 819 A1 A1 820 A1 821 A1 822 A1 A1 823 A1 A1824 A1 825 A1 826 A1 827 A1 828 A1 829 A1 830 A1

In some embodiments, the invention provides a compound selected from anyone of compound numbers 182, 187, 191, 207, 212, 219, 222, 223, 224,225, 226, 227, 229, 234, 235, 236, 241, 242, 243, 246, 248, 249, 250,251, 252, 253, 255, 256, 257, 258, 259, 260, 261, and 262.

In some embodiments, the invention provides a compound selected from anyone of compound numbers 263, 265, 266, 269, 271, 275, 276, 277, 280,283, 285, 286, 287, 288, 289, 290, 292, 293, 294, 295, 296, 297, 299,301, 302, 303, 304, 307, 308, 309, 312, 313, 315, 318, 319, 320, 321,322, 323, 325, 326, 328, 330, 331, 333, 335, 338, 340, 341, 342, 343,345, 346, 347, 348, 350, 351, 352, 353, 356, 358, 359, 360, 361, 362,363, 364, 372, 373, 374, 376, 377, 378, 380, 381, 382, 383, 384, 386,387, 388, 389, 390, 391, 392, 393, 396, 397, 398, 402, 403, 405, 406,407, 408, 409, 410, 411, 412, 415, 417, 418, 419, 420, 424, 427, 428,429, 433, 434, 436, 438, 439, 440, 442, 443, 444, 445, 446, 448, 451,452, 453, 454, 456, 457, 458, 459, 460, 463, 466, 468, 469, 470, 471,472, 473, 474, 475, 476, 480, 481, 482, 483, 485, 487, 488, 491, 494,497, 498, 500, 503, 505, 508, 511, 512, 514, 516, 517, 518, 521, 524,525, 527, 528, 529, 530, 531, 532, 534, 535, 536, 537, 538, 539, 540,541, 542, 544, 546, 547, 549, 551, 552, 553, 554, 555, 556, 557, 558,559, 560, 561, 562, 563, 564, 565, 566, 568, 569, 570, 571, 572, 573,574, 575, 577, 578, 579, 580, 581, 582, 585, 586, 587, 588, 589, 590,591, 592, 594, 595, 596, 597, 598, 599, 601, 602, 603, 604, 605, 606,607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620,621, 624, 625, 626, 627, 628, 629, 631, 632, 633, 634, 635, 636, 637,638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651,652, 653, 654, 655, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666,667, 668, 669, 670, 671, 674, 675, 676, 677, 678, 679, 680, 681, 682,683, 684, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697,698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712,713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726,727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740,741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754,755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768,769, 770, 771, 773, 774, 775, 776, 777, 778, 780, 781, 782, 784, 785,786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799,800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 811, 812, 813, 815,817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, and830.

Example 13 Cellular Assays for IDH1m (R132H or R132C) Inhibitors

Cells (e.g., HT1080 or U87MG) and are grown in T125 flasks in DMEMcontaining 10% FBS, 1× penicillin/streptomycin and 500 ug/mL G418. Theyare harvested by trypsin and seeded into 96 well white bottom plates ata density of 5000 cell/well in 100 ul/well in DMEM with 10% FBS. Nocells are plates in columns 1 and 12. Cells are incubated overnight at37° C. in 5% CO2. The next day compounds are made up at 2× concentrationand 100 ul are added to each cell well. The final concentration of DMSOis 0.2% and the DMSO control wells are plated in row G. The plates arethen placed in the incubator for 48 hours. At 48 hours, 100 μl of mediais removed from each well and analyzed by LC-MS for 2-HG concentrations.The cell plate is placed back in the incubator for another 24 hours. At72 hours post compound addition, 10 mL/plate of Promega Cell Titer Gloreagent is thawed and mixed. The cell plate is removed from theincubator and allowed to equilibrate to room temperature. Then 100 ul ofreagent is added to each well of media. The cell plate is then placed onan orbital shaker for 10 minutes and then allowed to sit at roomtemperature for 20 minutes. The plate is then read for luminescence withan integration time of 500 ms.

The IC₅₀ for inhibition of 2-HG production (concentration of testcompound to reduce 2HG production by 50% compared to control) in thesetwo cell lines for various compounds of formula I is set forth in Table4 above.

Example 14 Preparation of 2,3,5,6-Tetrasubstituted Pyridines Generalprocedure 1

Step A: 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (2)

To a solution of 1-cyclopropylethanone (100 g, 1.2 mol) in anhydrous DMF(1300 mL) Was added DMFDMA (300 g, 2.5 mol). The resulting mixture wasstirred at 100° C. overnight. The solvent was removed in vacuum to givecrude 2 (110 g) as yellow solid. ¹H NMR (CHLOROFORM-d) δ 7.56 (d, J=12.8Hz, 1H), 5.20 (d, J=12.5 Hz, 1H), 2.78-3.08 (m, 6H), 1.79 (tt, J=7.9,4.5 Hz, 1H), 0.94-1.04 (m, 2H), 0.67-0.80 (m, 2H).

Step B: 6-cyclopropyl-2-hydroxynicotinonitrile (3)

To a mixture of 1-cyclopropyl-3-dimethylamino-propenone (315 g, 2.3 mol)and cyanoacetamide (270 g, 2.3 mol) in a buffer solution of 47.4 mL ofacetic acid and 1485 mL of water was added piperidine to adjust to pH 9.The mixture was then heated at reflux for 2 hours, cooled and acidifiedby 6N HCl to pH 5 below 25 degree. The yellow precipitate was filtered,washed with water and dried to give 3 as a white solid (561 g). MS (ES)M+H expected 161.1, found 161.0. ¹H NMR (CHLOROFORM-d)

13.60 (br. s., 1H), 7.77 (d, J=7.8 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H),1.96-2.12 (m, 1H), 1.29-1.36 (m, 2H), 1.04-1.11 (m, 2H).

Step C: 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (4)

A mixture of 6-cyclopropyl-2-hydroxynicotinonitrile (561 g, 3.6 mol) andNBS (624 g, 5.4 mol) in DCE (4500 mL) was heated at reflux for 3 hrs.The mixture was cooled to room temperature and the precipitate wasfiltered, washed with water and dried to give crude 4 (473 g) as a whitesolid. MS (ES) M+H expected 239.0, found 238.9. ¹H NMR (CHLOROFORM-d) δ8.49-8.72 (br. s., 1H), 7.93 (s, 1H), 2.23-2.34 (m, 1H), 1.36-1.42 (m,2H), 1.29-1.36 (m, 2H).

Step D: 5-bromo-3-cyano-6-cyclopropylpyridin-2-yltrifluoromethanesulfonate (5)

To a 1 L flask were added 5-bromo-4-cyclopropyl-2-hydroxybenzonitrile(47.6 g, 0.2 mol), pyridine (32 g, 0.4 mol) and Cat. DMAP (500 mg) inDCM (300 mL), and the mixture was cooled to 0° C., andtrifluoromethanesulfonic anhydride (59 g, 0.21 mol) in DCM (100 mL) wasadded dropwise. After addition, the mixture was stirred for another 1 h.TLC (PE:EtOAc=10:1) showed conversion of starting material to product.After reaction, diluted with DCM (300 mL), and washed with 1N HCl. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo affordedthe title compound (70 g) as a yellow solid. ¹H NMR (CHLOROFORM-d) δ8.14-8.19 (m, 1H), 2.55-2.66 (m, 1H), 1.30 (dt, J=7.8, 3.1 Hz, 2H),1.21-1.27 (m, 2H).

Step E: Exemplified by(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(6-1) (R′=methyl)

A mixture of above triflate 5 (1.68 g, 4.6 mmol), (R)-2-methylpiperazine(790 mg, 6.9 mmol), and triethylamine (1.9 mL, 13.8 mmol) suspended in 5mL of MeCN was heated at 70° C. for 2 h. After the mixture wasconcentrated under reduced pressure, the residue was extracted betweenethyl acetate and water. The combined organic layer was then washed withaq. NaHCO₃, brine, dried over anhy. Na₂SO₄ and concentrated in vacuo togive 1.26 g of crude title compound. MS (ES) M+H expected 321.1, found321.2. ¹H NMR (CHLOROFORM-d) δ 7.78 (s, 1H), 4.14-4.24 (m, 2H),3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd,J=12.9, 10.2 Hz, 1H), 2.42-2.52 (m, 1H), 1.16 (d, J=6.3 Hz, 3H), 1.08(s, 2H), 1.07 (d, J=3.8 Hz, 2H).

(R)-5-bromo-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)nicotinonitrile(6-2) (R′=isopropyl) was synthesized by the same procedure describedabove except using (R)-2-isopropylpiperazine instead of(R)-2-methylpiperazine. MS (ES) M+H expected 349.1, found 349.2. ¹H NMR(CHLOROFORM-d)

7.79 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H),2.96-3.00 (m, 2H), 2.71 (dd, 1H), 2.12-2.22 (m, 1H), 1.26 (d, 6H), 1.08(d, 2H), 1.07 (d, 2H).

(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile(6-3) (R′=cyclopropyl) was synthesized by the same procedure describedabove except using (R)-2-cyclopropylpiperazine (building block 1)instead of (R)-2-methylpiperazine. MS (ES) M+H expected 347.1, found349.1. ¹H NMR (CHLOROFORM-d)

7.77 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H),2.96-3.00 (m, 2H), 2.71 (dd, 1H), 2.12-2.24 (m, 1H), 1.25 (d, 2H), 1.16(d, 2H), 1.08 (d, 2H), 1.07 (d, 2H).

Step F, method 1: Exemplified by(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7-1) (R′=methyl, R1=c)

To a 25 mL of round-bottom flask was added(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(6-1) (1.26 g, 3.9 mmol), 3-methoxypropanoic acid (0.74 mL, 7.8 mmol),HATU (2.98 g, 7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL of methylenechloride. The resulting reaction mixture was stirred at room temperatureovernight until TLC showed the completion of the reaction. Reactionmixture was with satd. NaHCO₃ and brine. The combined organic layer wasthen dried over anhy. Na₂SO₄ and concentrated in vacuo. Columnchromatography purification (30% EtOAc/petroleum ether) afforded 1.28 gof title compound as a white solid. MS (ES) M+H expected 407.1, found407.0. ¹H NMR (CHLOROFORM-d)

7.78-7.85 (m, 1H), 4.82-4.92 (m, 0.5H), 4.50 (d, J=13.6 Hz, 0.5H),4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H), 3.75-3.82 (m, 0.5H), 3.70-3.75 (m,2H), 3.45-3.55 (m, 0.5H), 3.36 (s, 3H), 3.15-3.27 (m, 1H), 2.92-3.14 (m,1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d,J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08(s, 2H).

Step F, Method 2: Exemplified by(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(7-2) (R′=methyl,

To a 25 mL of round-bottom flask was added(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(6-1) (1 g, 3.2 mmol), cyclopropanecarbonyl chloride (0.4 mL, 3.3 mmol),DIPEA (0.4 mL, 3.4 mmol) and 10 mL of methylene chloride. The resultingreaction mixture was stirred at room temperature overnight until TLCshowed the completion of the reaction. Reaction mixture was with Satd.NaHCO₃ and brine. The combined organic layer was then dried over anhy.Na₂SO₄ and concentrated in vacuo. Column chromatography purification(10% EtOAc/petroleum ether) afforded 1.1 g of title compound as a whitesolid. MS (ES) M+H expected 389.1, found 389.0. ¹H NMR (CHLOROFORM-d)

7.85 (s, 1H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H), 3.70-3.75 (m, 2H),3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m,1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz,1.5H), 1.25-1.36 (m, 4H), 1.09 (d, 2H), 1.08 (d, 2H).

Step F, method 3: Exemplified by(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7-3) (R′=methyl,

To a 25 mL of round-bottom flask was added(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(6-1) (2 g, 6.2 mmol), sodium 2-carboxyethanolate (0.70 g, 6.4 mmol),DIPEA (2 mL, 11.5 mmol) and 10 mL of DMF. The resulting reaction mixturewas stirred at room temperature for 5 h until TLC showed the completionof the reaction. Reaction mixture was washed with water and brine. Thecombined organic layer was then dried over anhy. Na₂SO₄ and concentratedin vacuo. Column chromatography purification (50% EtOAc/petroleum ether)afforded 1.2 g of title compound as a white solid. MS (ES) M+H expected393.1, found 393.1. ¹H NMR (CHLOROFORM-d) δ 7.85 (m, 1H), 4.88-4.97 (m,0.5H), 4.75 (d, J=13.6 Hz, 0.5H), 4.29-4.48 (m, 2H), 4.11-4.20 (m, 1H),3.70-3.75 (m, 2H), 3.45-3.55 (m, 2H), 3.15-3.27 (m, 1H), 2.92-3.14 (m,1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d,J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08(s, 2H).

(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile(7-4) was synthesized by method 1 in step F except using 6-3 as thestarting material instead of 6-1. MS (ES) M+H expected 433.1, found433.3.

(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(7-5) was synthesized by method 2 in step F except using 6-3 as thestarting material instead of 6-1. MS (ES) M+H expected 415.1, found415.1.

(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile(7-6) was synthesized by method 3 in step F except using 6-3 as thestarting material instead of 6-1. MS (ES) M+H expected 419.1, found419.1. ¹H NMR (CHLOROFORM-d) δ 7.85 (m, 1H), 4.87-4.97 (m, 0.5H), 4.77(d, J=13.6 Hz, 0.5H), 4.29-4.48 (m, 2H), 4.11-4.20 (m, 1H), 3.70-3.75(m, 2H), 3.45-3.55 (m, 2H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H),2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8Hz, 2H), 1.25 (d, 2H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).

(R)-5-bromo-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile(7-7) was synthesized by method 1 in step F except using 6-2 as thestarting material instead of 6-1. MS (ES) M+H expected 434.1, found435.1.

(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)nicotinonitrile(7-8) was synthesized by method 1 in step F except using 6-2 as thestarting material instead of 6-1. MS (ES) M+H expected 421.1, found421.6.

Step G, method 1: Exemplified by(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(8-1) (R′=methyl, R1=c)

To a solution of(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7-1) (747 mg, 1.8 mmol) in DMF (8 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2 dioxaborolane) (563 mg, 2.2mmol) and KOAc (538 mg, 5.5 mmol). The resulting mixture was stirred atroom temperature for 5 min before addition of PdCl₂(dppf).CH₂Cl₂ (45 mg,0.03 mmol). After flushing with nitrogen, the reaction mixture washeated at 85° C. for 18 hours. After cooling, the reaction mixture wasdiluted with water, and extracted with methylene chloride. The organiclayer was then washed with brine, dried over anhy. Na₂SO₄, andconcentrated in vacuo. Column chromatography (25% EtOAc/petroleum ether)afforded 334 mg of title compound as a white solid. MS (ES) M+H expected455.3, found 455.2.

Step G, method 2: Exemplified by(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(R′=methyl,

1.4 g of(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(7-3) (3.3 mmol), 2.12 g of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.34 mmol),0.7 g of KOAc (7.4 mmol), 154 mg of Xphos (0.32 mmol) and 308 mg ofPd₂(dba)₃ (0.33 mmol) in 20 mL of dioxane in a round bottom flask wasstirred under N₂ at 75° C. overnight. Then the mixture was cooled toroom temperature. Concentrated, purified by column chromatography(petroleum ether: ethyl acetate from 3:1 to 1:1) to give 670 mg of titlecompound. MS (ES) M+H expected 441.2, found 441.2.

General procedure 1, Step H: Exemplified by(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(thiophen-2-yl)nicotinonitrile(Compound 273)

A mixture of 7-1 (26 mg, 0.06 mmol), thiophen-2-ylboronic acid (14 mg,0.089 mmol), Pd(PPh₃)₄ (3 mg, 0.003 mmol), and K₂CO₃ (16 mg, 0.119 mmol)suspended in 1 mL of DMF was subjected to microwave reaction at 150° C.for 45 min. After the reaction was complete, the reaction mixture wasconcentrated in vacuo, and the residue was purified by columnChromatography to afford 19 mg of title compound as yellowish oil. ¹HNMR (CHLOROFORM-d) δ 7.70 (s, 1H), 7.38 (dd, J=3.9, 2.4 Hz, 1H),7.07-7.14 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H),4.15-4.41 (m, 2.5H), 3.67-3.89 (m, 2.5H), 3.47-3.63 (m, 0.5H), 3.34-3.43(m, 3H), 3.20-3.33 (m, 1H), 2.99-3.17 (m, 1.5H), 2.63-2.81 (m, 1H),2.50-2.62 (m, 1H), 2.26-2.36 (m, 1H), 1.37 (d, J=6.3 Hz, 1.5H), 1.27 (d,J=6.8 Hz, 1.5H), 1.10-1.18 (m, 2H), 0.94-1.05 (m, 2H). LC-MS: m/z 411.1(M+H)⁺.

Step I: Exemplifiedby(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile(Compound 603)

To a solution of 8-1 (95 mg, 0.197 mmol), 5-chloro-2-vinylquinazoline(25 mg, 0.131 mmol), Xphos (7 mg, 0.013 mmol), Pd₂(dba)₃ (6 mg, 0.007mmol) and K₃PO₄.H₂O (105 mg, 0.393 mmol) was stirred at 100° C. for 16hours, the mixture was partitioned between EtOAc and water, the organicwas washed with water, brine and concentrated to give the crude whichwas purified by column chromatography to give 25 mg of the product. ¹HNMR (CHLOROFORM-d) δ 9.16 (d, J=3.0 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H),7.95 (dd, J=8.5, 7.3 Hz, 1H), 7.66 (s, 1H), 7.45-7.58 (m, 1H), 7.06 (dd,J=17.2, 10.4 Hz, 1H), 6.80 (dd, J=17.3, 1.5 Hz, 1H), 5.80-5.96 (m, 1H),4.87-5.02 (m, 0.5H), 4.56 (d, J=12.0 Hz, 0.5H), 4.35-4.44 (m, 2.5H),3.84 (d, J=12.8 Hz, 0.5H), 3.69-3.79 (m, 2H), 3.52-3.65 (m, 0.5H),3.30-3.43 (m, 4H), 3.05-3.24 (m, 1.5H), 2.65-2.81 (m, 1H), 2.48-2.64 (m,1H), 1.50-1.59 (m, 1H), 1.30-1.44 (m, 3H), 1.13-1.22 (m, 2H), 0.84-0.89(m, 2H). LC-MS: m/z 483.2 (M+H)⁺

General Procedure 2

Step J: Exemplified by (R)-tert-butyl4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiper-azine-1-carboxylate(9-1, R′=cyclopropyl)

To a solution of 6-3 (1 g, 2.24 mmol) in DCM (8 mL) was added (Boc)₂O(0.5 g, 2.26 mmol) and Et₃N (0.1 mL). The resultant solution was stirredat room temperature for 2 h. The reaction mixture was diluted withwater. The organic layer was then washed with brine, dried over anhy.Na₂SO₄, and concentrated in vacuo to give the title compound as a whitesolid (1.5 g), which can be used directly for the next step. ¹H NMR(CHLOROFORM-d) δ 7.85 (s, 1H), 4.14-4.24 (m, 2H), 3.29-3.34 (m, 1H),3.12-3.18 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, 1H), 2.12-2.24 (m, 1H),1.5 (s, 9H), 1.25 (d, 2H), 1.16 (d, 2H), 1.08 (d, 2H), 1.07 (d, 2H).

Step K: Exemplified by (R)-tert-butyl4-(5-cyano-2-cyclopropyl-[3,3′-bipyridin]-6-yl)-2-cyclopropylpiperazine-1-carboxylate (R′=cyclopropyl, R4=3-pyridinyl)

To a solution of (R)-tert-butyl4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(150 mg, 0.33 mmol) in 2 mL of dioxane and 0.5 mL water was addedpyridin-3-ylboronic acid (45.6 mg, 0.37 mmol), Pd(dppf)Cl2 (24 mg, 0.033mmol), CsF (100 mg, 0.66 mmol). The resulting mixture was stirred at100° C. under N2 atmosphere and microwaved for 1 h. After TLC showed thecomplete conversion of starting material to product, the reactionmixture was concentrated and purified by column chromatography (20%EtOAc/petroleum ether) to afford 100 mg title compound. MS (ES) M+Hexpected 446.2, found 446.3.

Step L: Exemplified by(R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-[3,3′-bipyridine]-5-carbonitrile(R′=cyclopropyl, R4=3-pyridinyl)

To a solution of (R)-tert-butyl4-(5-cyano-2-cyclopropyl-[3,3′-bipyridin]-6-yl)-2-cyclopropylpiperazine-1-carboxylate (100 mg, 0.22 mmol) in 3 mL of DCM was addedTFA (1 mL). The resulting mixture was stirred at room temperature for 2h. After TLC showed the complete conversion of starting material toproduct, the reaction mixture was concentrated and basified with Na₂CO₃solution to pH=8. Then the solution was extracted with DCM (10 mL×3).The organic layer was dried and concentrated and purified by Prep-HPLC(5% DCM/MeOH) to get 70 mg title compound. MS (ES) M+H expected 346.2,found 346.2.

General Procedure 2, Step M: Exemplified by(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-[3,3′-bipyridine]-5-carbonitrile(Compound 524)

To a solution of(R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-[3,3′-bipyridine]-5-carbonitrile(70 mg, 0.2 mmol) in 10 mL DCM was added 3,3,3-trifluoropropanoic acid(31 mg, 0.24 mmol), and triethylamine (1 mL), HOBT (54 mg, 0.4 mmol),EDCI (76.8 mg, 0.4 mmol). The resulting reaction mixture was stirred atr.t. overnight. After TLC showed the complete conversion of startingmaterial to product, the reaction mixture was concentrated and purifiedby Prep-HPLC (50% EtOAc/petroleum ether) to get 25 mg title compound. ¹HNMR (CHLOROFORM-d) δ 8.56-8.77 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 7.65 (s,1H), 7.44 (dd, J=7.7, 4.9 Hz, 1H), 4.56 (d, J=13.1 Hz, 1H), 4.44 (d,J=13.1 Hz, 1H), 4.12 (br. s., 1H), 3.63-3.86 (m, 2H), 3.32 (d, J=9.3 Hz,2H), 3.20 (d, J=13.1 Hz, 1H), 3.11 (d, J=11.8 Hz, 1H), 1.99 (td, J=8.0,3.8 Hz, 1H), 1.11-1.23 (m, 3H), 1.01 (dd, J=7.5, 3.5 Hz, 2H), 0.77-0.95(m, 2H), 0.66 (br. s., 1H), 0.50 (d, J=5.0 Hz, 2H) LC-MS: m/z 4 456.4(M+H)⁺.

General Procedure 3

Method 1: Exemplified by(R)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)acetamide(Compound 403) (R″=H,

To a solution of(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (50 mg, 0.119 mmol) and 2-chloroacetylchloride (15 mg, 0.131 mmol) in 2 ml of DCM was added dropwise TEA (24mg, 0.238 mmol) at 0° C., then the mixture was allowed to warm to roomtemperature and stirred for 2 hours. The mixture was partitioned betweenEtOAc and water. The organic layer was dried over Na₂SO₄ andconcentrated to give the crude which was purified by prep-TLC to give 20mg of the product. ¹H NMR (CHLOROFORM-d) δ 8.34 (s, 1H), 7.66-7.75 (m,1H), 7.62 (s, 1H), 7.50-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.22 (d, J=7.8Hz, 1H), 4.92 (s, 0.5H), 4.50-4.54 (m, 0.5H), 4.29-4.33 (m, 1H), 4.26(m, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.84 (m, 2.5H), 3.52-3.57 (m, 0.5H),3.39 (s, 3H), 3.21-3.32 (m, 1H), 3.13 (d, J=11.3 Hz, 1H), 3.05 (d,J=12.3 Hz, 0.5H), 2.66-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.07-2.12 (m,1H), 1.40 (d, J=6.3 Hz, 1H), 1.28-1.31 (m, 2H), 1.14-1.19 (m, 2H),0.94-1.00 (m, 2H). LC-MS: m/z 496.2 (M+H)⁺.

Method 2: Exemplified by(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)propionamide(Compound 424)

To a 25 mL of round-bottom flask was added(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (50 mg, 0.119 mmol), propionic acid (0.1mL), HATU (20 mg), DIPEA (0.05 mL) and 10 mL of methylene chloride. Theresulting reaction mixture was stirred at room temperature overnightuntil TLC showed the completion of the reaction. Reaction mixture waswith satd. NaHCO₃ and brine. The combined organic layer was then driedover anhy. Na₂SO₄ and concentrated in vacuo. Column chromatographypurification (30% EtOAc/petroleum ether) afforded 45 mg of titlecompound as a white solid. ¹H NMR (CHLOROFORM-d) 7.75 (s, 1H), 7.68 (s,1H), 7.59 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.11(d, J=7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.14-4.35(m, 2.5H), 3.67-3.85 (m, 2.5H), 3.49-3.62 (m, 0.5H), 3.37 (s, 3H),3.17-3.32 (m, 1H), 2.93-3.17 (m, 1.5H), 2.63-2.81 (m, 1H), 2.52-2.63 (m,1H), 2.37-2.49 (m, 2H), 2.05-2.13 (m, 1H), 1.38 (d, J=6.5 Hz, 1H),1.22-1.31 (m, 5H), 1.14 (dt, J=7.4, 3.6 Hz, 2H), 0.88-1.01 (m, 2H).LC-MS: m/z 476.3 (M+H)⁺.

General Procedure 4

Step O: 5-bromo-3-cyano-6-cyclopropylpyridin-2-yl4-methylbenzenesulfonate (10)

To a solution of 4 (2.37 g, 10 mmol) in THF (20 mL) was added TsCl (1.9g, 11 mmol) and Et₃N (1 mL). The reaction was stirred at roomtemperature for 2 h. The resultant solution was partitioned between DCMand water. The organic layer was dried over Na₂SO₄ and concentrated togive the crude which was purified by column chromatography to give 2.6 gof 10. ¹H NMR (CHLOROFORM-d) δ 7.86 (s, 1H), 7.35-7.46 (m, 2H),7.11-7.25 (m, 2H), 1.99-2.17 (m, 1H), 1.21-1.38 (m, 2H), 1.00-1.20 (m,2H). LC-MS: m/z 393.0 (M+H)⁺.

Step P: Exemplified by6-cyclopropyl-5-(4-fluorophenyl)-2-hydroxynicotinonitrile (1H)

A mixture of 10 (2.6 g, 11 mmol), 4-fluorophenylboronic acid (1.4 g, 10mmol), Pd(PPh₃)₄ (30 mg), and K₂CO₃ (16 mg, 0.119 mmol) suspended in 10mL of DMF was subjected to microwave reaction at 150° C. for 45 min.After the reaction, the reaction mixture was concentrated in vacuo, andthe residue was purified by column chromatography to afford 1.9 g oftitle compound as a yellow solid. LC-MS: m/z 255.0 (M+H)⁺

Step Q

3-cyano-6-cyclopropyl-5-(4-fluorophenyl)pyridin-2-yltrifluoromethanesulfonate. ¹H NMR (CHLOROFORM-d) δ: 7.87 (s, 1H),7.32-7.57 (m, 2H), 7.13-7.24 (m, 2H), 1.99-2.17 (m, 1H), 1.21-1.38 (m,2H), 1.00-1.20 (m, 2H). LC-MS: m/z 387.1 (M+H)⁺.

Step R

The same procedure as General procedure 1, step E except using 12-1 asthe starting material instead of 5 and the suitable building blocksdescribed in the “building block” section.

Step S

The same procedure as General procedure 1, step G except using thesuitable building blocks described in the “building block” section.

General Procedure 5

Step T: Exemplified by (R)-tert-butyl4-(2′-chloro-5-cyano-2-cyclopropyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazine-1-carboxylate

To a 25 mL flask was added with 9-1 (1000 mg 2.235 mmol),2-chloropyridin-4-ylboronic acid (457 mg, 2.906 mmol), Pd(PPh₃)₄ (120mg, 0.1 mmol), K₂CO₃ (926 mg, 6.705 mmol), and 4 mL DMF. The resultantmixture was stirred at 150° C. for 5 h. After washing with satd. NaHCO₃,brine, the combined organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo. Column chromatography purification (20%EtOAc/petroleum ether) afforded 640 mg of title compound. ¹H NMR(CHLOROFORM-d) δ 8.48 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.39-7.47 (m,1H), 7.32 (dd, J=5.1, 1.3 Hz, 1H), 4.59 (d, J=12.9 Hz, 1H), 4.45 (d,J=13.2 Hz, 1H), 4.09 (d, J=13.5 Hz, 1H), 3.50 (d, J=9.1 Hz, 1H),3.34-3.43 (m, 1H), 3.27 (dd, J=13.2, 3.8 Hz, 1H), 3.11 (td, J=12.5, 3.7Hz, 1H), 1.94-2.06 (m, 1H), 1.77 (br. s., 2H), 1.50 (s, 9H), 1.34 (br.s., 1H), 1.04 (dd, J=7.9, 3.2 Hz, 2H), 0.56-0.63 (m, 2H), 0.50 (dd,J=8.5, 3.5 Hz, 1H), 0.32-0.42 (m, 1H).

Step U: Exemplified by(R)-tert-butyl-4-(5-cyano-2-cyclopropyl-2′-vinyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazine-1-carboxylate

To a flask was added with (R)-tert-butyl4-(2′-chloro-5-cyano-2-cyclopropyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazine-1-carboxylate(640 mg 1.33 mmol), tributyl(vinyl)stannane (550 mg, 1.73 mmol),Pd(PPh₃)₄ (120 mg, 0.1 mmol), K₂CO₃ (460 mg, 3.33 mmol), and 4 mL DMF.The resultant mixture was stirred at 150° C. for 5 h. After washing withsatd. NaHCO₃, brine, the combined organic layer was dried over anhy.Na₂SO₄ and concentrated in vacuo. Column chromatography purification(20% EtOAc/petroleum ether) afforded the compound. LC-MS: m/z 472.2(M+H)⁺.

Step V:(R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

To a flask was added (R)-tert-butyl4-(5-cyano-2-cyclopropyl-2′-vinyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazine-1-carboxylateand 12 mL EtOH/HCl (1M). The resulting reaction mixture was stirred at0° C. for 30 minutes until TLC showed the completion of the reaction,which was concentrated in vacuo to afford a product as light yellowishsolid. ¹H NMR (CHLOROFORM-d) δ: 8.65 (d, J=5.0 Hz, 1H), 7.62 (s, 1H),7.38 (s, 1H), 7.23 (dd, J=5.0, 1.8 Hz, 1H), 6.89 (dd, J=17.3, 10.9 Hz,1H), 6.29 (dd, J=17.6, 1.2 Hz, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H), 4.50(d, J=12.9 Hz, 1H), 4.36 (d, J=13.2 Hz, 1H), 3.28 (br. s., 1H), 3.22 (d,J=12.3 Hz, 1H), 3.10 (br. s., 1H), 2.95 (br. s., 1H), 1.96-2.06 (m, 1H),1.21 (t, J=4.1 Hz, 1H), 0.95-1.07 (m, 3H), 0.92 (br. s., 1H), 0.62 (d,J=7.9 Hz, 2H), 0.40 (d, J=4.7 Hz, 2H).

Step W

The same procedure as General procedure 1, step G except using thesuitable building blocks described in the “building block” section.

General Procedure 6

Step A′: 1-cyclopropylbutane-1,3-dione

A mixture of CH3ONa (75.65 g, 1.25 mol) and 1-cyclopropylethanone (105.0g, 1.25 mol) in THF (1000 mL) was stirred at 35° C. for 1 h and followedby addition of ethyl acetate (110.0 g, 1.25 mol) dropwise. Afterstirring at 50° C. for 4 hrs, the solvent was removed under reducedpressure and the residue was dissolved in H2O (500 mL) and adjusted topH 3.5 with citric acid. The mixture was extracted by ethyl acetate (500mL×3). The combined organic layers were concentrated in vacuum to give1-cyclopropylbutane-1,3-dione (110.0 g, yield 69%) as a yellow oil. ¹HNMR (CHLOROFORM-d) δ 0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m,1H), 2.00 (s, 3H).

Step B′: 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile

A mixture of 1-cyclopropylbutane-1,3-dione (126.0 g, 1.0 mol) and2-cyanoacetamide (88.0 g, 1.0 mol) and piperidine (60 mL) in EtOH (1500mL) was stirred at reflux for 4 hrs. The reaction mixture was filtered,washed with PE (200 mL) and dried in vacuum to give6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (90.0 g, 52%) as a whitesolid. ¹H NMR (DMSO-d6) δ 12.36 (br. s., 1H), 5.93 (s, 1H), 2.26 (s,3H), 1.81-1.91 (m, 1H), 1.06-1.14 (m, 2H), 0.91-0.95 (m, 2H).

Step C′: 5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile

A mixture of 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (90.0 g,0.52 mol) and NBS (100.0 g, 0.57 mol) in DCE (1500 mL) was stirred atreflux temperature for 4 hrs. The reaction mixture was filtered and theresidue was washed with DCE (200 mL) and dried in vacuum to give5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (100.0 g, 76%)as a white solid. MS (ES) M+H expected 253.0, found 253.0. ¹H NMR(CHLOROFORM-d) δ 2.68 (s, 3H), 1.79-1.88 (m, 1H), 1.03-1.09 (m, 2H),0.93-1.01 (m, 2H).

Step D′: 5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yltrifluoromethane-sulfonate

To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (40 g,0.15 mol) in 200 mL of methylene chloride was added DMAP (1.78 g, 14.6mmol), and triethylamine (25 mL, 175 mmol). The mixture was cooled to 0°C. in an ice-water bath, and trifluoromethanesulfonic anhydride (37 mL,0.21 mol) was added dropwise by syringe. The resulting reaction mixturewas stirred at 0° C. for 30 min then allowed to warm to room temperatureand stirred overnight. After TLC showed the complete conversion ofstarting material to product, the reaction mixture was concentrated andpurified by column chromatography (20% EtOAc/petroleum ether) to afford55 g of title compound. ¹H NMR (CHLOROFORM-d). 2.70 (s, 3H), 2.16-2.20(m, 1H), 1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H)

Step E′: Exemplified by(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(R′″=methyl)

A mixture of 5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yltrifluoromethanesulfonate (50.0 g, 0.13 mol) and (R)-2-methylpiperazine(15.6 g, 0.16 mol) and Et3N (26.0 g, 0.26 mol) in THF (500 mL) wasstirred at 80° C. overnight. The resulting mixture concentrated invacuum to give(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitrile(34.8 g, 80%) as a white solid. ¹H NMR (CHLOROFORM-d) δ 4.08-4.16 (m,0.5H), 4.05-4.08 (m, 1H), 4.01-4.04 (m, 0.5H), 2.99-3.08 (m, 1H), 2.97(d, J=8.8 Hz, 2H), 2.88-2.95 (m, 1H), 2.58-2.65 (m, 1H), 2.55-2.57 (m,3H), 1.77 (br. s., 1H), 1.12 (s, 1.5H), 1.10 (s, 1.5H), 1.05-1.09 (m,2H), 1.00-1.05 (m, 2H).

Step F′: preparation of(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(R′″=methyl,

A mixture of (R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (34.8 g, 0.1 mol) and 3-methoxypropanoicacid (16.0 g, 0.15 mol) in pyridine (500 mL) was stirred at 0° C. for 30min, and followed by addition of POCl₃ (28.7 g, 0.19 mol) dropwise. Theresulting mixture was stirred at 20° C. for 2 hrs. The reaction mixturewas concentrated and purified by chromatography to give(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile(25.0 g, 59%) as yellow oil.

¹H NMR (CHLOROFORM-d) δ 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H),4.22 (br. s., 0.5H), 3.95-4.13 (m, 2H), 3.78 (br. s., 0.5H), 3.74 (t,J=5.9 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H), 3.07-3.24 (m, 1.5H),2.90-3.06 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (s, 3H), 2.52-2.63 (m, 1H),2.17-2.21 (m, 1H), 1.37 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.3 Hz, 1.5H),1.09 (s, 2H), 1.05-1.08 (m, 2H).

Step G′ was similar to Step H in general procedure 1.

General Procedure 7

Step H′: 6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile

To a solution of 6-cyclopropyl-2-hydroxynicotinonitrile (20 g, 0.125mmol) in Ac₂O (110 mL) was added dropwise HNO₃ (15 mL) at 0° C.˜40° C.for 30 mins. After the addition, the reaction mixture was stirred atr.t. for 3 hrs. The mixture was cooled to 0° C. and the solid wascollected by filtration. The solid was washed with brine dried undervacuum to give the title compound (15.5 g, 60.4%) as a pale yellowsolid. ¹H NMR (CHLOROFORM-d) δ10.71 (s, 1H), 8.68 (s, 1H), 3.13 (tt,J=8.6, 5.6 Hz, 1H), 1.57-1.52 (m, 2H), 1.44-1.37 (m, 2H). LC-MS: m/z205.9 (M+H)⁺

Step I′: 3-cyano-6-cyclopropyl-5-nitropyridin-2-yltrifluoromethanesulfonate

To a solution of 6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile (7.6 g,37.7 mmol) in DCM (150 mL) was added DMAP (30.0 mg) and TEA (7.5 g, 74.1mmol) at r.t. Then Tf₂O (15.7 g, 55.6 mmol) was added dropwise to theabove solution at −40° C. for 30 min. The reaction mixture was stirredat −40° C. for 2 hs. The mixture was quenched with water at −40° C. Themixture was then extracted with EtOAc (50 mL×2). The combined organiclayer was washed with brine, dried over Na₂SO₄. The organic phase wasfiltered and the filtrate was concentrated in vacuum to give the titlecompound (12.5 g, crude) as a pale yellow solid. LC-MS: m/z 337.5 (M+H)⁺

Step J′:(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-nitronicotinonitrile

To a solution of 3-cyano-6-cyclopropyl-5-nitropyridin-2-yltrifluoromethanesulfonate (10.9 g, 32.3 mmol) and(R)-2-isopropylpiperazine (3.45 g, 27.0 mmol) in CH₃CN (100 mL) wasadded TEA (6.5 g, 64.7 mmol) at r.t. The reaction mixture was heated andstirred at 85° C. for 3 hrs. The mixture was concentrated in vacuo andthe residue was extracted with EtOAc (50 mL×2). The combined organiclayer was washed with brine, dried over Na₂SO₄. The organic phase wasfiltered and the filtrate was concentrated in vacuum to give the titlecompound (8.5 g, crude) as a brown solid. LC-MS: m/z 316.6 (M+H)⁺

Step K′: (R)-tert-butyl4-(3-cyano-6-cyclopropyl-5-nitropyridin-2-yl)-2-isopropylpiperazine-1-carboxylate

To a solution of(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-nitronicotinonitrile(8.52 g, 26.2 mmol) and Boc anhydride (8.5 g, 39.3 mmol) in DCM (50 mL)was added TEA (3.9 g, 39.3 mmol) at r.t. The reaction mixture wasstirred at 30° C. for 3 hrs. The solvent was removed in vacuum and theresidue was purified via silica gel column chromatography (DCM:MeOH) toafford the title compound (10.4 g, 95%) as a yellow liquid. ¹H NMR(CHLOROFORM-d) δ 8.51 (s, 1H), 4.74 (d, J=13.7 Hz, 1H), 4.55 (d, J=13.1Hz, 1H), 3.88 (s, 1H), 3.37-3.23 (m, 2H), 3.11 (ddd, J=10.5, 7.7, 5.7Hz, 2H), 1.86 (tdd, J=13.3, 8.5, 4.9 Hz, 1H), 1.49 (s, 9H), 1.27 (d,J=2.3 Hz, 2H), 1.26-1.17 (m, 4H), 1.01 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.8Hz, 3H).

Step L′: (R)-tert-butyl4-(5-amino-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-carboxylate

To a solution of (R)-tert-butyl4-(3-cyano-6-cyclopropyl-5-nitropyridin-2-yl)-2-isopropylpiperazine-1-carboxylate(19 g, 45.8 mmol) in EtOH (200 mL) and H₂O (100 mL) was added Zinc (30g, 458 mmol) and NH₄Cl (24.5 g, 458 mmol) at r.t. The reaction mixturewas stirred at 40° C. overnight. The mixture was filtered through a padof silica and the filtrate was extracted with EtOAc (100 mL×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄. Theorganic phase was filtered and the filtrate was concentrated in vacuumto give the title compound (13.1 g, 74.3%) as a yellow solid. ¹H NMR(CHLOROFORM-d) δ: 7.10 (d, J=2.9 Hz, 1H), 4.02 (t, J=19.0 Hz, 3H), 3.81(t, J=16.8 Hz, 3H), 3.13 (td, J=12.8, 2.4 Hz, 1H), 2.99-2.86 (m, 2H),2.25 (tt, J=12.9, 6.5 Hz, 1H), 1.97-1.83 (m, 1H), 1.49 (d, J=2.2 Hz,9H), 1.13-1.06 (m, 2H), 1.06-1.01 (m, 2H), 0.98 (t, J=9.2 Hz, 3H), 0.87(t, J=6.6 Hz, 3H). LC-MS: m/z 386.6 (M+H)⁺

Step M′: (R)-tert-butyl4-(5-((4-chloropyridin-2-yl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-carboxylate

To a solution of (R)-tert-butyl4-(5-amino-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-carboxylate(600 mg, 81.6 mmol) and 2-bromo-4-chloropyridine (390.3 mg, 2.03 mmol)in 1,4-dioxane (15 mL) was added Pd₂(dba)₃ (142.7 mg, 0.156 mmol) andXantphos (135.3 mg, 0.234 mmol) and Cs₂CO₃ (1.02 g, 3.12 mmol) at r.t.under N₂. The resulting mixture was heated and stirred at 115° C. underN₂ in microwave for 1 h. The solvent was removed in vacuum and theresidue was purified via reverse phase silica gel column chromatography(MeOH:H₂O) to afford the title compound (137 mg, 18%) as a pale yellowsolid. ¹H NMR (CHLOROFORM-d) δ: 8.07 (d, J=5.4 Hz, 1H), 7.72 (d, J=3.3Hz, 1H), 6.75 (dd, J=5.5, 1.7 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 6.25 (s,1H), 4.45 (d, J=13.2 Hz, 1H), 4.26 (d, J=9.2 Hz, 1H), 4.21-3.61 (m,2.5H), 3.11 (dt, J=13.5, 6.8 Hz, 2.5H), 2.22-1.98 (m, 2H), 1.52-1.47 (m,9H), 1.28 (s, 1H), 1.14 (dt, J=8.1, 4.5 Hz, 1H), 1.08 (dd, J=9.7, 4.7Hz, 1H), 1.01 (dd, J=10.9, 5.2 Hz, 4H), 0.90 (d, J=6.8 Hz, 3H). LC-MS:m/z 497.6 (M+H)⁺

Step N′: (R)-tert-butyl4-(3-cyano-6-cyclopropyl-5-((4-vinylpyridin-2-yl)amino)pyridin-2-yl)-2-isopropylpiperazine-1-carboxylate

To a solution of (R)-tert-butyl4-(5-((4-chloropyridin-2-yl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-carboxylate(600 mg, 1.21 mmol) in isopropanol (15 mL) and H₂O (3 mL) was addedVinyltrifluoroboric acid potassium salt (324.2 mg, 2.42 mmol),Pd(dppf)Cl₂ (98.7 mg, 0.121 mmol) and DIPEA (312.2 mg, 2.42 mmol) atr.t. under N₂. The reaction mixture was heated and stirred at 125° C.under N₂ in microwave for 1.5 h. The solvent was removed in vacuum andthe residue was purified via silica gel column chromatography (DCM:MeOH)to afford the title compound (513 mg, 87%) as a yellow solid. LC-MS: m/z489.6 (M+H)⁺

Step O′:(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

To a solution of (R)-tert-butyl4-(3-cyano-6-cyclopropyl-5-((4-vinylpyridin-2-yl)amino)pyridin-2-yl)-2-isopropylpiperazine-1-carboxylate(513 mg, 1.05 mmol) in anhydrous DCM (10 mL) was added TFA (5 mL) atr.t. The reaction mixture was stirred at r.t. for 2 hs. The solvent wasremoved in vacuum and the residue was adjusted to pH>7.0. The residuemixture was extracted with EtOAc (15 mL×2). The combined organic layerwas washed with brine, dried over Na₂SO₄. The organic phase was filteredand the filtrate was concentrated in vacuum to give out the titlecompound (crude, 406 mg) as a yellow liquid. ¹H NMR (CHLOROFORM-d) δ:7.99 (d, J=6.6 Hz, 1H), 7.72 (s, 1H), 7.04 (dd, J=6.6, 1.3 Hz, 1H), 6.64(dd, J=17.4, 10.8 Hz, 1H), 6.47 (s, 1H), 6.12 (d, J=17.5 Hz, 1H), 5.81(d, J=10.8 Hz, 1H), 5.24 (s, 1H), 4.59 (d, J=13.9 Hz, 1H), 4.45 (d,J=14.3 Hz, 1H), 3.63-3.48 (m, 2H), 3.30 (dd, J=14.1, 11.1 Hz, 2H), 3.18(s, 1H), 2.15-2.01 (m, 2H), 1.28 (d, J=4.8 Hz, 1H), 1.16 (dd, J=10.2,6.9 Hz, 8H), 1.12-1.09 (m, 1H). LC-MS: m/z 389.5 (M+H)⁺

Step P′:(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile(Compound 757)

To a solution of(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile(300 mg, 0.77 mmol) in DMF (15 mL) was added sodium 3-hydroxypropanoate(208.8 mg, 1.55 mmol), HATU (442.5 mg, 1.2 mmol) and DIPEA (200 mg, 1.55mmol) at r.t. The reaction mixture was stirred at r.t. for 3 hs. Thesolvent was removed in vacuum and the residue was purified via silicagel column chromatography (DCM: MeOH) to afford the title compound (138mg, 38.8%) as a pale yellow solid. ¹H NMR (CHLOROFORM-d) δ: 8.12 (d,J=5.4 Hz, 1H), 7.85 (d, J=5.5 Hz, 1H), 6.84 (d, J=5.4 Hz, 1H), 6.59 (dd,J=17.6, 10.8 Hz, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 5.91 (d, J=17.5 Hz,1H), 5.48 (d, J=10.9 Hz, 1H), 4.69 (d, J=10.4 Hz, 0.5H), 4.44 (d, J=12.6Hz, 1.5H), 4.31-4.23 (m, 1H), 3.93 (s, 2H), 3.75 (d, J=13.5 Hz, 0.5H),3.51-3.38 (m, 2H), 3.14-2.97 (m, 2H), 2.61 (dt, J=5.7, 4.8 Hz, 2H),2.36-2.25 (m, 0.5H), 2.19 (ddd, J=12.9, 8.1, 4.9 Hz, 1H), 1.29 (t,J=16.6 Hz, 1H), 1.18-0.97 (m, 7H), 0.95-0.88 (m, 1.5H), 0.86 (d, J=6.8Hz, 1.5H). LC-MS: m/z 461.6 (M+H)⁺

General Procedure 8

Step Q′: ((R)-tert-butyl4-(3-cyano-6-cyclopropyl-5-hydroxypyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate

To a mixture of (R)-tert-butyl4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(0.35 g, 1.0 mmol), potassium hydroxide (0.22 g, 4 mmol) in a 50 mLflask was added Pd₂(dba)₃ (0.092 g, 0.1 mmol), t-Bu-Xphos (0.082 g, 0.2mol). Then 10 mL 1,4-dioxane and 1.0 mL water was added, the mixture wasstirred at 80° C. for 16 hours, cooled and acidified with 2N HCl to pH 6(temperature held below 25° C.). Then the mixture was extracted withethyl acetate (15 mL×2), the organic phase was combined and concentratedto give brown oil, which was further purified by silica gelchromatography (PE:EA=3:1), to give 0.16 g of (1) as a white solid (41%yield). LC-MS: m/z 386.0 (M+H)⁺

Step R′: (R)-tert-butyl4-(5-(2-chloropyridin-4-yloxy)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate

A mixture of (R)-tert-butyl4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate (0.16 g, 0.41 mol), 2-chloro-4-iodopyridine(0.15 g, 0.62 mol), 9 mg Cu(I)Br (0.06 mmol) and 12 mg2,2,6,6-tetramethylheptane-3,5-dione (0.06 mmol), 0.28 g Cs₂CO₃ washeated under microwave in 4 mL DMSO for 30 min. The mixture was cooledto room temperature and washed with water and purified by silica gelchromatography (DCM: MeOH=20:1) to give 0.10 g of (2) as a yellow solid(52% yield). LC-MS: m/z 486.0 (M+H)⁺

Step S′:(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile

A mixture of (R)-tert-butyl4-(5-(2-chloropyridin-4-yloxy)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(0.10 g, 0.21 mmol) and TFA (0.35 mL) was stirred in DCM (10 mL) for 2hrs. The solvent was removed and the residue was basified with NaHCO₃solution and extracted with DCM (10 mL), the organic phase was separatedand concentrated to give a yellow solid (3) (0.075 g, 0.19 mmol, crudeyield 90%). LC-MS: m/z 397.1 (M+H)⁺

Step T′:(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile(Compound 694)

A mixture of(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile(0.35 g, 0.88 mmol), sodium 3-hydroxypropanoate (0.10 g, 0.88 mmol),HATU (0.50 g, 1.32 mmol) and 0.23 g DIEA (1.76 mmol) was stirred in 8 mLDMF for 4 hrs. Then the mixture was quenched by adding 6 mL water andextracted with EA (15 mL×2), the organic phase was combined andconcentrated to give a yellow oil, which was further purified by silicagel chromatography (DCM:MeOH=20:1) to give 0.10 g of product as a yellowsolid (52% yield). ¹H NMR (CHLOROFORM-d) δ: 8.30 (d, J=5.6 Hz, 1H),7.48-7.49 (m, 0.5H), 6.81 (dt, J=5.6, 2.0 Hz, 2H), 4.70 (s, 1H), 4.41(d, J=13.0 Hz, 1H), 4.29 (d, J=13.0 Hz, 1H), 4.12 (dd, J=18.6, 7.4 Hz,1H), 3.93 (s, 2H), 3.84-3.67 (m, 1H), 3.18 (d, J=12.8 Hz, 1H), 3.13-2.99(m, 1H), 2.61 (s, 2H), 2.32-2.22 (m, 0.5H), 2.02 (t, J=4.6 Hz, 1H), 1.35(s, 1H), 1.29 (d, J=9.4 Hz, 3H), 1.14 (dd, J=7.4, 3.0 Hz, 2H), 1.04 (dt,J=7.9, 3.1 Hz, 2H), 0.66-0.67 (m, 2H), 0.46-0.51 (m, 2H). LC-MS: m/z468.1 (M+H)⁺

Step U′:(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylpyridin-4-yloxy)nicotinonitrile(Compound 692)

A mixture of(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (4) 0.35 g, (0.75 mmol),potassium trifluoro(vinyl)borate (0.15 g, 1.1 mmol), PdCl₂dppf (80 mg,0.075 mmol) and DIEA (0.24 mL, 1.5 mmol) was heated in isopropanol atreflux at 85° C. under nitrogen for 5 hrs. Then mixture was thenconcentrated under reduced pressure to give a yellow solid which wasfurther purified by silica chromatography (PE/EA/MeOH=150/120/8) to give0.19 g of product as a white solid (55% yield). ¹H NMR (CHLOROFORM-d) δ:8.47 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.86 (d, J=2.3 Hz, 1H),6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22 (dd,J=17.4, 0.9 Hz, 1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.68 (d, J=11.7 Hz,1H), 4.38 (d, J=12.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.15-4.04 (m, 1H), 3.92(s, 2H), 3.75 (d, J=20.7 Hz, 1H), 3.47 (d, J=21.7 Hz, 1H), 3.25-3.12 (m,1H), 3.09-2.95 (m, 1H), 2.60 (s, 2H), 2.32-2.22 (m, 0.5H), 2.11-2.05 (m,1H), 1.37 (d, J=20.5 Hz, 1H), 1.27 (d, J=2.0 Hz, 1H), 1.16-1.10 (m, 2H),1.01 (ddd, J=10.1, 6.7, 3.3 Hz, 2H), 0.65 (t, J=33.7 Hz, 2H), 0.45-0.48(m, 2H). LC-MS: m/z 460.1 (M+H)⁺

General Procedure 9

Core 7-1 (120 mg, 0.295 mmol) and amine (0.295 mmol) were dissolved intoluene (2 mL). K3PO4 (125.0 mg, 0.590 mmol), Xantphos (cat.) andPd2(dba)3(cat.) were added to above mixture under N2. The mixture wasshaken at 120° C. for 16 hrs. The crude product was purified byprep-HPLC.

Example 15 Building Blocks Syntheses Building Block 1:(R)-2-cyclopropylpiperazine

Step 1

To a solution of(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile(100 g, 0.87 mol) in water (1250 ml), NaHCO₃ (175 g, 2.08 mol) was addat room temperature, then a solution of (Boc)₂O in THF (1250 mL) wasadded and the reaction mixture was heated to reflux overnight. Then theresulting mixture was concentrated to remove THF under reduced pressure.EtOAc (1250 mL) was added to the residue and the resulting mixture wascooled to 5° C. and then adjusted to pH 3 with saturated aqueous NaHSO₄.The layers were separated and the aqueous was extracted with EtOAc (1000mL×3). The combined EtOAc layers were washed with water and brine, driedover Na₂SO₄ and concentrated under reduced pressure to give(R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (165 g, yield88%). ¹H NMR (MeOD 400 MHz) 3.16-3.14 (d, J=8.8, 1H), 1.11 (s, 9H),0.73-0.78 (m, 1H), 0.28-0.2 (m, 3H), 0.18-0.15 (m, 1H) 100 ee %.

Step 2

Isobutyl chloroformate (81.6 g, 0.6 mol.) was added over 1 hr to astirred mixture of (R)-2-(tert-butoxycarbonylamino)-2-cyclopropylaceticacid (129 g, 0.6 mol.) and Et₃N (67 g, 0.66 mol.) in DCM (1000 mL) at 0°C.-5° C. and the reaction mixture was stirred 1 hr at 0° C.-5° C. In aseparate flask, a mixture of glycine methyl ester hydrochloride (82.8 g,0.66 mol.), Et₃N (73 g, 0.72 mol.) and DCM (1000 mL) was stirred for 1hr and the mixture was then added to the flask over 2 hrs. After theaddition was complete, the mixture was stirred overnight at roomtemperature for 40 hrs and then washed with water and brine, dried withNa₂SO₄, concentrated under reduced pressure and the residue was purifiedby column chromatography to give (R)-methyl2-(2-(tert-butoxycarbonylamino)-2-cyclopropyl acetamido)acetate (100 g,yield 58%) as white solid. 100 ee %. ¹H NMR (DMSO 400 MHz) δ 8.2-8.16(t, J=5.6, 1H), 6.66-6.86 (d, J=8.8, 9H), 3.71-3.92 (m, 2H), 3.62 (s,3H), 3.46-3.51 (t, J=8.4, 1H), 1.36 (s, 9H), 0.97-1.01 (m, 1H),0.38-0.44 (m, 3H), 0.25-0.28 (m, 1H).

Step 3

To a solution of (R)-methyl2-(2-(tert-butoxycarbonylamino)-2-cyclopropylacetamido) acetate (290 g,1.014 mol) in DCM (1740 mL), TFA (870 mL) was added dropwise at 0° C.The reaction solution was stirred overnight at room temperature. Theresulting solution was concentrated under reduced pressure to give(R)-methyl 2-(2-amino-2-cyclopropylacetamido) acetate (511 g crude).

Step 4

To a solution (R)-methyl 2-(2-amino-2-cyclopropylacetamido)acetate(255.5 g crude, 0.507 mol) in MeOH (1250 ml), Et₃N (750 ml, 10.78 mol)was added was added dropwise at 0° C. Then the reaction solution wasstirred two days at room temperature. The resulting mixture was filteredand the precipitate was washed with MTBE and dried by high vacuum togive (R)-3-cyclopropylpiperazine-2,5-dione (60 g, yield 76.9%). ¹H NMR(DMSO 400 MHz) δ 7.98 (s, 1H), 7.74 (s, 1H), 3.68-6.64 (d, J=17.6, 1H),3.30-3.36 (m, 1H), 2.9-2.93 (dd, J=3.2, 1H), 0.87-0.92 (m, 1H),0.21-0.27 (m, 3H), 0.18-0.21 (m, 1H).

Step 5

To a suspension mixture of (R)-3-cyclopropylpiperazine-2,5-dione (30 g,0.195 mmol) in THF (1000 mL), AlLiH₄ (45 g, 1.184 mol) was added inportions over 1.5 hrs at 0° C. Then the reaction mixture was heated to70° C. overnight. After cooling, water (45 mL) was added dropwise at 0°C. and then a solution of KOH (45 mL, 1%) was added dropwise at 0° C.The resulting mixture was filtered and the residue was washed with EtOAcand MeOH (3:1) and the filtrate was concentrated under reduced pressureto give crude product. Then the crude product was washed with DCM andthe filtrate was concentrated under reduced pressure to give(R)-2-cyclopropylpiperazine (18.5 g, yield 75.5%). 99.5 ee %. ¹H NMR(MeOD 400 MHz) δ 2.9-2.96 (m, 1H), 2.8-2.88 (m, 1H), 2.7-2.8 (m, 1H),2.55-2.68 (m, 2H), 2.4-2.5 (q, J=10.4, 1H), 1.65-1.73 (m, 1H), 0.55-0.67(m, 1H), 0.35-0.45 (m, 2H), 0.05-0.25 (m, 2H).

Building Block 2: 2-(2,2,2-trifluoroethyl)piperazine

Step 1

To a solution of 2-amino-4,4,4-trifluorobutanoic acid (450 mg, 3 mmol)in 5 mL H₂O and 5 mL THF was added NaHCO₃ (504 mg, 6 mmol), followed bya solution of di-tert-butyl dicarbonate (650 mg, 3 mmol) in THF (3 mL).The resulting mixture was stirred at 80° C. overnight. After removal ofTHF, poured into water and extracted with methylene chloride. Thecombined organic layer was dried over anhy. Na₂SO₄ and concentrated invacuo. 723 mg of 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoicacid was obtained as a crude product and used in subsequent reactionwithout further purification. MS (ES) M+H expected 258, found 258. ¹HNMR (CHLOROFORM-d)

5.25 (d, J=7.8 Hz, 1H), 4.40-4.67 (m, 1H), 2.60-2.90 (m, 2H), 1.46 (s,9H).

Step 2

To a 25 mL of round-bottom flask was added2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (723 mg, 2.8mmol), Et₃N (560 mg, 5.6 mmol), isobutyl carbonochloridate (380 g, 2.8mmol) in 5 mL methylene chloride. The resulting reaction mixture wasstirred at 0° C. for 0.5 hours. And methyl 2-aminoacetate (352 mg, 2.8mmol) was added. The resulting mixture was stirred at room temperatureovernight. After washing with Satd. NaHCO₃, brine, the combined organiclayer was dried over anhy. Na₂SO₄ and concentrated in vacuo. 900 mg ofmethyl 2-(2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanamido)acetatewas obtained as a crude product and used in subsequent reaction withoutfurther purification. MS (ES) M+H expected 329.1, found 329.0. ¹H NMR(CHLOROFORM-d) δ 7.11 (br. s., 1H), 5.28 (br. s., 1H), 4.44-4.67 (m,1H), 3.84-4.07 (m, 2H), 3.69-3.83 (s, 3H), 2.72-2.95 (m, 1H), 2.42-2.64(m, 1H), 1.38-1.50 (m, 9H).

Step 3

A mixture of methyl2-(2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanamido)acetate (900mg, 2.7 mmol) in 5 mL 1,2-dichlorobenzene was heated to 180° C.overnight. The mixture was cooled down and was added MTBE (5 mL). Abrown yellowish precipitate was formed. The filter cake was washed withMTBE and air-dried to give 200 mg of3-(2,2,2-trifluoroethyl)piperazine-2,5-dione. ¹H NMR (DMSO-d6) δ 8.28(d, J=9.3 Hz, 2H), 4.00-4.26 (m, 1H), 3.68-3.87 (m, 2H), 2.66-2.88 (m,2H).

Step 4

To a flask was added 3-(2,2,2-trifluoroethyl)piperazine-2,5-dione (200mg, 1 mmol) in TH F(5 mL), and LAH (2.5 mL, 6 mmol) was added dropwiseunder N₂ at 0° C. And the mixture was heated to 65° C. overnight. Afterreaction, the mixture was cooled down. And 0.23 mL H₂O was addedfollowed by 0.2×3 mL 10% NaOH and 0.46 mL H₂O, and the mixture wasfiltered. The cake washed with EtOAc. The organic phase was concentratedto give 2-(2,2,2-trifluoroethyl)piperazine 140 mg, which was usedwithout further purification. 1H NMR (CHLOROFORM-d) δ 2.75-3.02 (m, 7H),2.52 (dd, J=11.7, 9.9 Hz, 1H), 2.10-2.17 (m, 2H).

Building Block 3: 2-(difluoromethyl)piperazine

To a solution of 1,4-dibenzyl-2-(difluoromethyl)piperazine (synthesizedaccording to Synthetic Communications, 2011, vol. 41, #14, 2031-2035)(80mg, 0.253 mmol) in 40 mL of EtOH was added Pd(OH)₂/C (15 mg). Theresulting mixture was hydrogenated under 50 Psi at r.t. for two days.The reaction mixture was filtered, and the filtrate was concentrated toafford 2-(difluoromethyl)piperazine, which was used directly withoutfurther purification. LC-MS: m/z 137.1 (M+H)⁺

Building Block 4: 6-fluoro-1,4-diazepane

Step 1

To a solution of 1,4-ditosyl-1,4-diazepan-6-ol (synthesized according toSynthesis, 2003, 2, 223-226) (200 mg, 0.47 mmol) in 5 mL of DCM wasadded DAST (190 mg, 1.18 mmol). The resulting mixture was stirred atr.t. overnight. The reaction mixture was quenched with aq NaHCO₃. Theaqueous layer was extracted with DCM and the combined organic phaseswere dried and concentrated. The residue was purified by prep-TLC toafford 6-fluoro-1,4-ditosyl-1,4-diazepane (120 mg). ¹H NMR(CHLOROFORM-d) δ 7.66-7.71 (m, 4H), 7.34 (d, J=8.0 Hz, 4H), 5.02-4.92(m, 1H), 3.60 (dd, J=18.1, 5.3 Hz, 4H), 3.34-3.53 (m, 4H), 2.46 (s, 6H).

Step 2

A suspension of 6-fluoro-1,4-ditosyl-1,4-diazepane (82 mg, 0.19 mmol) inHOAc—HBr (3 mL, 30 wt %) was heated to 100° C. for 3 mins in a pressuretube using microwave irradiation. The solvent was removed in vacuum andthe residue triturated with Et₂O, washed with Et₂O to give6-fluoro-1,4-diazepane, which was used directly without furtherpurification. LC-MS: m/z 119.1 (M+H)⁺

Building Block 5: 6-fluoro-2-methyl-1,4-diazepane

Step 1

6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane (120 mg) was obtained from2-methyl-1,4-ditosyl-1,4-diazepan-6-ol (synthesized according toSynthesis, 2003, 2, 223-226) (200 mg, 0.47 mmol) (200 mg) by the methodsimilar to 6-fluoro-1,4-ditosyl-1,4-diazepane. ¹H NMR (CHLOROFORM-d) δ7.62-7.75 (m, 4H), 7.30-7.37 (m, 4H), 5.00-4.84 (m, 1H), 4.09-4.37 (m,2H), 3.73-3.95 (m, 1H), 3.37-3.62 (m, 2H), 3.12-3.32 (m, 1H), 3.05 (ddd,J=13.6, 7.2, 4.0 Hz, 1H), 2.43-2.46 (m, 6H), 1.05-1.14 (m, 3H).

Step 2

6-fluoro-2-methyl-1,4-diazepane was obtained from6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane by the method similar to6-fluoro-1,4-ditosyl-1,4-diazepane. LC-MS: m/z 133.1 (M+H)⁺

Building Block 6: 2-(oxetan-2-yl)acetic acid

Step 1

A mixture of 3-buten-1-ol (18.03 g, 0.25 mol), TEA (2.4 mL, 0.02 mol)and sodium hydroxide (15 g, 0.38 mol) in hexane (200 mL) was stirred at50° C. for 0.5 h. Benzyl bromide (32.7 mL, 0.27 mol) in hexane (50 mL)was added dropwise over a period of 0.5 h. Afterwards, the resultingmixture was heated to reflux overnight (oil temperature: 85° C.). Theprecipitate was removed via filtration and washed with ethyl acetatetwice. The combined organic phase was washed with brine and dried oversodium sulfate. Such obtained product was pure enough for the nextreaction step. Yield: 38.21 g, 94.2%, colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.46-7.29 (m, 6H), 5.89 (ddt, J=17.0, 10.1, 6.7 Hz, 1H),5.21-5.03 (m, 2H), 4.56 (s, 2H), 3.57 (t, J=6.8 Hz, 2H), 2.43 (qd,J=6.7, 1.1 Hz, 2H).

Step 2

To solution of ((but-3-en-1-yloxy)methyl)benzene (38.21 g, 0.24 mol) indichloromethane (400 mL) was added mCPBA (77.15 g, 0.38 mol) at −20° C.as solid in portions. Afterwards, the resulting suspension was allowedto warm to rt and stirred overnight. The precipitate was filtered offand washed with dichloromethane. Afterwards, the combined organic phasewas washed with saturated NaHCO3 and Na2SO3 and brine. The whiteprecipitate was occurred while removing solvents under reduced pressure.More n-hexane was added and the most appeared white solid was filteredoff. This procedure was repeated third times. The crude product wassubjected to column chromatography on silica gel using a mixture ofethyl acetate with petroleum ether as eluent (EtOAc:PE=1/50 to 1/5) toafford the title compound. Yield: 35.26 g, 84.0%, pale yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 7.41-7.29 (m, 5H), 4.56 (s, 2H), 3.73-3.59 (m,2H), 3.15-3.06 (m, 1H), 2.85-2.77 (m, 1H), 2.55 (dd, J=5.0, 2.7 Hz, 1H),1.95 (dddd, J=13.4, 7.2, 6.2, 4.7 Hz, 1H), 1.81 (dq, J=14.3, 5.9 Hz,1H). LC-MS: m/z 220.0 (M+CH₃CN)⁺.

Step 3

To a round bottom flask charged with HOAc (60.1 mg, 1.0 mol %) intoluene (20 mL) was added Jacobsen salen Co(II) catalyst (0.30 g, 0.5mol %) at rt and the resulting solution was stirred at rt for 0.5 hwhile the flask is open to air in order to absorb oxygen. The volatileswere removed under reduced pressure to give rise to a dark solid.Racemic epoxide (17.82 g, 100 mmol) was added neat, followed by theaddition of distilled water (1.0 mL, 56 mmol) dropwise at 0° C. Theresulting reaction mixture was allowed to warm to it slowly and stirredat it overnight. The reaction mixture was diluted with n-hexane and thenpassed through a pad of celite. Epoxide was obtained by using petroleumether and diol was obtained by using a mixture of methanol withdichloromethane (1/30). The obtained epoxide (red oil) was distilled andthe desired product was obtained at 145-165° C. (oil temperature);similarly, the diol was obtained at 185-205° C. (oil temperature). Yieldof epoxide: 7.83 g, 43.9%, pale yellow oil; Yield of diol: 8.46 g,43.1%, bright yellow oil. For chiral epoxide: ¹H NMR (400 MHz, CDCl₃) δ7.41-7.29 (m, 5H), 4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15-3.06 (m, 1H),2.85-2.77 (m, 1H), 2.55 (dd, J=5.0, 2.7 Hz, 1H), 1.95 (dddd, J=13.4,7.2, 6.2, 4.7 Hz, 1H), 1.81 (dq, J=14.3, 5.9 Hz, 1H). LC-MS: m/z 220.0(M+CH₃CN)⁺. For chiral diol: ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.29 (m,5H), 4.53 (s, 2H), 3.94 (s, 1H), 3.86-3.41 (m, 5H), 3.18 (s, 1H),1.91-1.66 (m, 2H). LC-MS: m/z 219.0 (M+Na)⁺. ee>99%.

Step 4

A mixture of potassium tert-butoxide (1.68 g, 15 mmol) andtrimethyloxosulphonium iodide (3.30 g, 15 mmol) in tert-butoxide (35 mL)was stirred at 50° C. for 1 h. A solution of chiral epoxide (0.89 g, 5mmol) in tert-butoxide (15 mL) was added dropwise while keeping thetemperature around 50° C. Afterwards, the resulting reaction mixture wasstirred at 50° C. overnight. The precipitate was removed via filtrationand washed with ethyl acetate. The combined organic phase was driedunder reduced pressure and diluted with ethyl acetate. The dilutedsolution was washed with brine and dried over sodium sulfate. The crudeproduct was subjected to column chromatography on silica gel usingEtOAc:PE=1/10 as eluent to afford the title compound. Yield: 0.55 g,57.7%; colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.29 (m, 5H),5.09-4.94 (m, 1H), 4.70 (dd, J=14.0, 7.8 Hz, 1H), 4.62-4.38 (m, 3H),3.67-3.51 (m, 2H), 2.72 (dq, J=13.9, 7.8 Hz, 1H), 2.43 (dt, J=10.7, 7.6Hz, 1H), 2.16 (td, J=13.3, 5.8 Hz, 1H), 2.02 (td, J=13.6, 6.0 Hz, 1H).LC-MS: m/z 234.1 (M+CH3CN)⁺. ee>99%.

Step 5

A mixture of (R)-2-(2-(benzyloxy)ethyl)oxetane (4.35 g, 22.63 mmol) andpalladium hydroxide on carbon (20%, with 50% of water, 0.80 g, 2.5 mol%) in methanol (50 mL) and dichloromethane (15 mL) was stirred at rtovernight with an input of hydrogen gas. The precipitate was removed viafiltration through a pad of celite and washed with dichloromethane. Thecombined organic phase was dried using water pump at 30° C. and wasconfirmed pure enough for the next reaction. Yield: 2.28 g, 98.7%;colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.09 (qd, J=7.5, 4.6 Hz, 1H),4.70 (td, J=8.0, 6.0 Hz, 1H), 4.57 (dt, J=9.1, 5.9 Hz, 1H), 3.82 (ddd,J=11.8, 7.3, 4.6 Hz, 1H), 3.74 (ddd, J=11.1, 6.5, 4.9 Hz, 1H), 3.11-2.77(m, 1H), 2.77-2.62 (m, 1H), 2.45 (ddt, J=11.0, 9.1, 7.4 Hz, 1H),2.13-1.98 (m, 1H), 1.91 (ddt, J=14.3, 7.3, 4.7 Hz, 1H). ee>99%.

Step 6

To a mixture of oxetane (3.10 g, 30.48 mmol), sodium periodate (19.56 g,91.44 mmol), water (30 mL), acetonitrile (60 mL) and carbontetrachloride (30 mL) was added ruthenium trichloride plus three water(79.7 mg, 1 mol %) at 0-5° C. Afterwards, the resulting mixture wasallowed to warm to rt and stirred at this temperature for 2 h. Theprecipitate was removed via filtration through a pad of celite andwashed with diethyl ether (around 100 mL×5). The combined organic phasewas washed with brine (50 mL×3) and then dried using water pump at 35°C. and was confirmed pure enough for the next reaction. Yield: 2.26 g,63.8%; light yellow oil. ¹H NMR (400 MHz, methanol-d4) δ 5.26-5.15 (m,1H), 4.69 (ddd, J=8.3, 7.8, 5.9 Hz, 1H), 4.58 (dt, J=9.2, 5.9 Hz, 1H),2.88-2.70 (m, 3H), 2.51 (ddt, J=11.2, 9.1, 7.3 Hz, 1H). ee>99%.

Building Block 7: 5-bromoisoquinoline 2-oxide

To a solution of 5-bromoisoquinoline (1.5 g, 7.2 mmol) indichloromethane (20 mL) was added mCPBA (1.5 g, 8.6 mmol) at roomtemperature all at once. The reaction mixture was stirred at roomtemperature for 2 h. Then the mixture was washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄. The solvent was removed and theresidue was purified by column chromatography over silica gel (EtOAc) togive 0.97 g of title compound as a pale yellow solid. ¹H NMR(CHLOROFORM-d) δ 8.71-8.80 (m, 1H), 8.22 (dd, J=7.3, 1.5 Hz, 1H), 8.06(d, J=7.3 Hz, 1H), 7.81-7.91 (m, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.43-7.54(m, 1H). LC-MS: m/z 222.9 (M+H)⁺

Building Block 8: 5-bromo-1-chloroisoquinoline

To a solution of 5-bromoisoquinoline 2-oxide (0.4 g, 2.4 mmol) in CHCl₃(10 mL) was added POCl₃ (0.7 mL, 3 eq). Then the mixture was refluxedfor 2 h. After cooling to room temperature, the reaction mixture waspoured into ice-water, neutralized with saturated NaHCO3 (aq), extractedwith EtOAc. The solvent was removed and 0.45 g crude product wasobtained which was used in next step with further purification. ¹H NMR(CHLOROFORM-d) δ 8.33-8.44 (m, 2H), 8.02-8.08 (m, 1H), 8.00 (d, J=5.6Hz, 1H), 7.52-7.61 (m, 1H). LC-MS: m/z 242.9 (M+H)⁺.

Building Block 9: 5-bromo-1-methoxyisoquinoline

To a solution of 5-bromo-1-chloroisoquinoline (1.2 g, 5.0 mmol) inmethanol (10 mL) was added NaOMe (324 mg, 6.0 mmol). The mixture wasrefluxed for 2 h. The solvent was removed and the residue was purifiedby column chromatography over silica gel (10-20% EtOAc/petroleum ether)to obtain 600 mg of title compound as a white solid. ¹H NMR (DMSO-d₆) δ8.26 (d, J=8.3 Hz, 1H), 8.12 (d, J=6.0 Hz, 1H), 7.95 (dd, J=7.5, 1.0 Hz,1H), 7.58 (d, J=6.0 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 4.17 (s, 3H).LC-MS: m/z 237.0 (M+H)⁺

Building Block 10: 5-bromo-1-methoxyisoquinoline

To a suspension of 5-bromo-1-chloroisoquinoline (300 mg, 1.2 mmol) inwater (10 mL) was added NaOH (240 mg, 6 mmol). The mixture was refluxedfor 2 h. After cooling to room temperature, the pH of the mixture wasadjusted to 7 with 2N HCl. The precipitate was filtered and dried to get205 mg crude product as a white solid which was used directly in nextstep. LC-MS: m/z 222.9 (M+H)⁺

Building Block 11: 5-bromo-1-methoxyisoquinoline

A mixture of 5-bromoisoquinoline 2-oxide (224 mg, 1.0 mmol), diethylphosphorocyanidate (489 mg, 3.0 mmol) and Et3N (101 mg, 1.0 mmol) inCH3CN (5 mL) was heated at 150° C. for 1.5 h in a microwave oven. Aftercooling to room temperature, the precipitate was filtered and dried toobtain 110 mg product as a yellow solid. ¹H NMR (CHLOROFORM-d) δ 8.79(d, J=5.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 8.14(d, J=7.5 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H). LC-MS: m/z 231.9 (M+H)⁺

Building Block 12: 5-bromo-3-chloroisoquinoline

Step 1

To a solution of 1,3-dichloroisoquinoline (4 g, 20.2 mmol) in CH3CN (100mL) was added H2SO4 (4 mL), followed by NBS (4.4 g, 24.2 mmol). Themixture was stirred at room temperature for 90 h. Then the precipitatewas collected by filtration, washed with water, dried to afford 3.4 g of5-bromo-1,3-dichloroisoquinoline as a pale yellow solid. ¹H NMR(CHLOROFORM-d) δ 8.33 (d, J=8.5 Hz, 1H), 8.03-8.10 (m, 2H), 7.56 (dd,J=8.4, 7.7 Hz, 1H). LC-MS: m/z 276.9 (M+H)⁺

Step 2

To a suspension of 5-bromo-1,3-dichloroisoquinoline (3 g, 10.8 mmol) inAcOH (30 mL) and conc. HCl (6 mL) was added Sn powder (3.86 g, 32.4mmol). The mixture was stirred at 60° C. for 20 min. After cooling toroom temperature, the mixture was neutralized with NaOH (aq), filteredthrough celite. The filtrate was extracted with EtOAc (2×30 mL). Thesolvent was removed and the residue was purified by columnchromatography over silica gel (5-10% EtOAc/petroleum ether) to afford0.8 g of 5-bromo-3-chloroisoquinoline as a white solid. ¹H NMR(CHLOROFORM-d) δ 9.04 (s, 1H), 8.04 (s, 1H), 7.90-8.02 (m, 2H), 7.47 (t,J=7.9 Hz, 1H).

Building Block 13: 4-chloro-2-vinyl-1,7-naphthyridine

Step 1

To a stirred solution of ethyl-2-aminonicotinate (1 g, 6.02 mmol) andethyl acetate (13 g, 147.7 mmol) in 15 mL of anhydrous THF was addedsodium tert-butoxide (1.45 g, 15.1 mmol) portionwise over 1 min. Theresulting mixture was stirred at room temperature for 40 mins and at100° C. for 4 hours. After this time the reaction was cooled to r.t. andevaporated in vacuo. The resulting solid was dissolved in water (20 mL)and neutralized to pH 7 with 1.0M aqueous HCl. The resulting solid wasfiltered and dried under vacuum overnight to give ethyl3-(3-acetamidoisonicotinamido)isonicotinate as a tan solid (0.58 g,59%). LC-MS: m/z 329.1 (M+H)⁺ ¹H NMR (CHLOROFORM-d) δ: 11.96 (s, 1H),10.74 (br. s., 1H), 10.12 (s, 1H), 9.99 (s, 1H), 8.56 (d, J=5.3 Hz, 1H),8.59 (d, J=5.0 Hz, 1H), 7.89-7.96 (m, 1H), 7.66 (d, J=5.3 Hz, 1H), 4.51(q, J=7.0 Hz, 2H), 2.24-2.33 (m, 3H), 2.19 (s, 2H), 1.43-1.54 (t, 3H).

Step 2

A stirred solution of ethyl 3-(3-acetamidoisonicotinamido)isonicotinate(400 mg, 2.47 mmol) in phosphorus oxychloride (2.5 mL) was heated to120° C. for 3 hours. After this time the reaction was cooled to r.t. andevaporated in vacuo. The resulting residue was carefully basified topH>10 with an aqueous solution of Na₂CO₃ and the resulting solid wasfiltered, washed with water and dried under vacuum to give2,4-dichloro-1,7-naphthyridine (200 mg, 83%). ¹H NMR (CHLOROFORM-d) δ:9.48 (s, 1H), 8.79 (d, J=5.9 Hz, 1H), 8.01 (d, J=5.9 Hz, 1H), 7.74 (s,1H). LC-MS: m/z 200 (M+H)⁺

Step 3

To 5 mg PdCl₂(dppf). CH₂Cl₂ in a reaction tube under nitrogen were added3 mL isopropanol, 1 mL water, 93.6 mg (0.8 mmol) DIPEA, 52 mg (0.39mmol) potassium vinyl trifluoroborate and 78 mg (0.39 mmol)4-chloro-2-vinyl-1,7-naphthyridine. The reaction solution was heated to100° C. for half hour under microwave irradiation. The reaction mixturewas extracted into ethyl acetate, washed several times with water andpurified by prepTLC (petrol: ethyl acetate=1:1) to give4-chloro-2-vinyl-1,7-naphthyridine 50 mg (66.8%). ¹H NMR (CHLOROFORM-d)δ: 9.51 (d, J=0.6 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 7.98-8.04 (m, 1H),7.89 (s, 1H), 7.02 (dd, J=17.6, 10.9 Hz, 1H), 6.41 (d, J=17.6 Hz, 1H),5.83 (d, J=11.2 Hz, 1H). LC-MS: m/z 191.6 (M+H)⁺

Building Block 14: 5-chloro-2-vinylquinoxaline

Step 1

To a solution of 5-chloroquinoxaline (1.4 g, 8.54 mmol) in 50 mL ofdichloromethane was added mCPBA (1.62 g, 9.39 mmol). The resultingmixture was stirred at room temperature overnight. After removal ofdichloromethane, the crude product obtained was purified by doing columnchromatography (100% DCM) to afford 1.5 g of 5-chloroquinoxaline 1-oxideas a white solid.

Step 2

To a solution of 5-chloroquinoxaline 1-oxide (450 mg, 2.5 mmol) in 5 mLof chloroform was added POCl₃ (1.9 g, 12.5 mmol) slowly. The resultingmixture was heated to 80° C. and held stirring at 80° C. overnight.After removal of chloroform and excess POCl₃, the crude product obtainedwas purified by doing column chromatography (5% PE/EA) to afford 240 mgof 2,5-dichloroquinoxaline as a white solid. MS (ES) M+H expected 198,found 199. ¹H NMR (CHLOROFORM-d) δ: 8.89 (s, 1H), 7.98 (d, 1H), 7.92 (d,1H), 7.76 (t, 1H).

Step 3

To a flask was added 2,5-dichloroquinoxaline (315 mg, 1.59 mmol),potassium trifluoro(vinyl)borate (234 mg, 1.75 mmol), PdCl₂DPPF (130 mg,0.16 mmol), K₂CO₃ (442 mg, 3.18 mmol), propan-2-ol (4 mL), and H₂O (1mL), the mixture was degassed with N₂, then heated to 90° C. withstirring for about 3 hrs. TLC (5% PE/EA) showed the consumption of thestarting material and new spot appeared. The mixture was then filteredthrough celite, the cake was washed with ethyl acetate. The filtrate wasconcentrated in vacuo, the residue was purified by column chromatography(1-5% PE/EA) to afford 256 mg of 5-chloro-2-vinylquinoxaline as a whitesolid. ¹H NMR (CHLOROFORM-d) δ: 9.10 (s, 1H), 8.02 (d, 1H), 7.85 (d,1H), 7.71 (t, 1H), 7.09 (q, 1H), 6.57 (d, 1H), 5.89 (d, 1H). MS (ES) M+Hexpected 190, found 191.

Building Block 15:2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(morpholin-2-yl)nicotinonitrile

Step 1

A mixture of 7-2 (500 mg, 1.28 mmol), Potassium vinyltrifluoroborate(258 mg, 1.93 mmol), TEA (650 mg, 6.4 mmol) and Pd(dppf)Cl₂(52 mg, 0.064mmol) in i-PrOH and water was heated at 100° C. under microwaveirradiation for 0.5 hr. The reaction mixture was concentrated and theresidue was purified by column chromatography (50% PE/EA) to afford 420mg of title compound. ¹H NMR (CHLOROFORM-d) δ 7.80 (s, 1H), 6.99 (dd,J=17.3, 10.8 Hz, 1H), 5.58 (dd, J=17.3, 0.8 Hz, 1H), 5.36 (dd, J=11.0,0.8 Hz, 1H), 4.86 (br. s., 0.5H), 4.53 (br. s., 0.5H), 4.44 (br. s.,0.5H), 4.09-4.29 (m, 2.5H), 3.65 (br. s., 0.5H), 3.41 (br. s., 0.5H),3.12-3.24 (m, 2H), 2.14-2.26 (m, 1H), 1.76 (br. s., 1H), 1.25-1.42 (m,3H), 1.10-1.17 (m, 2H), 0.96-1.10 (m, 4H), 0.82 (dd, J=7.8, 1.8 Hz, 2H).

Step 2

A mixture of(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-vinylnicotinonitrile(200 mg, 0.59 mmol), N-(2-hydroxyethyl)-4-nitrobenzenesulfonamide (174mg, 0.71 mmol, synthesized in accordance with Organic Letters, 2011, 13,#4, p. 728-731), and NIS (159 mg, 0.71 mmol) suspended in 10 mL of MeCNwas stirred at r.t. for 2 hrs. After the mixture was concentrated invacuo, the residue was purified by column chromatography (50% PE/EA) toafford 100 mg ofN-(2-(1-(5-cyano-6-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)-2-iodoethoxy)ethyl)-4-nitrobenzenesulfonamide as a lightyellowish solid. ¹H NMR (CHLOROFORM-d) δ 8.36-8.45 (m, J=8.8 Hz, 2H),8.08-8.17 (m, J=8.8 Hz, 2H), 7.60 (s, 1H), 5.57 (br. s., 1H), 4.83 (br.s., 0.5H), 4.60-4.71 (m, 1H), 4.53 (br. s., 0.5H), 4.40 (br. s., 0.5H),4.19-4.34 (m, 2.5H), 3.54-3.72 (m, 1H), 3.15-3.48 (m, 8H), 1.88-1.98 (m,1H), 1.75 (br. s., 1H), 1.34-1.40 (m, 3H), 1.00-1.18 (m, 6H), 0.81 (d,J=7.8 Hz, 2H).

Step 3

A mixture ofN-(2-(1-(5-cyano-6-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)-2-iodoethoxy)ethyl)-4-nitrobenzenesulfonamide(100 mg, 0.14 mmol), K₂CO₃ (97 mg, 0.71 mmol) in 10 mL of MeCN wasstirred at r.t. overnight. After the mixture was filtered, the filtratewas concentrated and the residue was purified by column chromatography(50% PE/EA) to afford 66 mg of2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(4-((4-nitrophenyl)sulfonyl)morpholin-2-yl)nicotinonitrileas a light yellowish solid. ¹H NMR (CHLOROFORM-d) δ 8.39-8.49 (m, J=8.5Hz, 2H), 7.90-8.02 (m, J=8.3 Hz, 2H), 7.70 (s, 1H), 4.91 (dd, J=10.2,2.1 Hz, 1H), 4.84 (br. s., 0.5H), 4.52 (br. s., 0.5H), 4.42 (br. s.,0.5H), 4.16 (dd, J=11.8, 2.5 Hz, 4H), 3.86-4.00 (m, 2H), 3.76 (d, J=11.5Hz, 1H), 3.61 (br. s., 0.5H), 3.14-3.38 (m, 3H), 2.52-2.69 (m, 1H),1.97-2.09 (m, 1H), 1.74 (br. s., 1H), 1.28-1.48 (m, 3H), 1.19-1.25 (m,2H), 1.11-1.19 (m, 2H), 1.04-1.11 (m, 2H), 0.81 (d, J=7.5 Hz, 2H).

Step 4

A mixture of2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(4-((4-nitrophenyl)sulfonyl)morpholin-2-yl)nicotinonitrile(50 mg, 0.075 mmol), butane-1-thiol (3 d) and LiOH.H₂O(20 mg) in 10 mLof MeCN was stirred at r.t. overnight. After the mixture was filtered,the filtrate was concentrated and the residue was purified by columnchromatography (10% DCM/MeOH) to afford 21 mg of2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(morpholin-2-yl)nicotinonitrile.¹H NMR (CHLOROFORM-d) δ 7.81 (br. s., 1H), 4.96 (br. s., 1H), 4.34-4.63(m, 1H), 4.14 (br. s., 3H), 3.97 (br. s., 1H), 3.46 (br. s., 3H), 3.32(br. s., 2H), 3.09 (br. s., 3H), 2.75 (br. s., 1H), 2.09 (br. s., 1H),1.74 (br. s., 1H), 1.26 (br. s., 5H), 1.03 (br. s., 4H), 0.80 (br. s.,2H).

Building Block 16: 5-chloro-2-vinylquinazoline

Step 1

To a solution of 1-chloro-2-methyl-3-nitrobenzene (10.0 g, 58.3 mmol) in150 mL of anhydrous DMF was added 1,1-dimethoxy-N,N-dimethylmethanamine(21.0 g, 175 mmol). The resulting mixture was stirred at 140° C. for 16hours. After cooling to 0° C., the mixture was added slowly a solutionof NaIO₄ (37.4 g, 175 mmol) in H₂O and DMF. The mixture was stirred foranother 6 hours. The mixture was filtered and partitioned between EtOAcand water. The organic layer was washed with water and dried over Na₂SO₄and concentrated to give the crude which was purified by column toafford 6.5 g of 2-chloro-6-nitrobenzaldehyde. ¹H NMR (CHLOROFORM-d) δ10.39 (s, 1H), 7.95-8.04 (m, 1H), 7.74-7.80 (m, 1H), 7.64 (t, J=8.0 Hz,1H). LC-MS: m/z 186.0 (M+H)⁺

Step 2

To a solution of 2-chloro-6-nitrobenzaldehyde (1 g, 0.0054 mmol) inethanol was added Fe (1.8 g, 0.032 mmol), AcOH (10 ml) and 2N aqueousHCl (5 mL). The resulting mixture was stirred at 25° C. for 2 hours. Themixture was filtered and the filtrate was partitioned between DCM andwater, the organic layer was washed with water and brine, concentratedto give 2-amino-6-chlorobenzaldehyde under 25° C. which was withoutpurification for next step. LC-MS: m/z 156.01 (M+H).

Step 3

The mixture of compound 2-amino-6-chlorobenzaldehyde (2.8 g, 0.018 mol),guanidine (3.43 g, 0.36 mol) and Na₂CO₃ (3.82 g, 0.36 mol) innaphthalene was stirred at 180° C. for 2 hours. After cooling to roomtemperature, the mixture was filtered and the solid was washed withwater and DCM to give the yellow solid 5-chloroquinazolin-2-amine whichwas used without purification for next step. ¹H NMR (DMSO-d6) δ9.28 (s,1H), 7.65 (dd, J=8.5, 7.8 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.31 (d,J=7.5 Hz, 1H), 7.16 (s, 2H). LC-MS: m/z 180.0 (M+H).

Step 4

The mixture of 5-chloroquinazolin-2-amine (2.2 g, 12.2 mmol), isoamylnitrite (4.30 g, 36.7 mmol), CuI (1.17 g, 6.12 mmol) and CH₂I₂ (16.4 g,61.2 mmol) in THF was stirred at 60° C. for 72 hours. After cooling toroom temperature, the mixture was filtered and the filtrate waspartitioned between EtOAc and water, the organic layer was washed withwater and brine, dried over Na₂SO₄. Then the organic layer wasconcentrate to give the crude which was purified by column to give5-chloro-2-iodoquinazoline as yellow solid. ¹H NMR (CHLOROFORM-d)

9.46 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.86 (dd, J=8.5, 7.5 Hz, 1H), 7.72(dd, J=7.4, 1.1 Hz, 1H).

LC-MS: m/z 291.1 (M+H).

Step 5

The mixture of 5-chloro-2-iodoquinazoline (1.3 g, 4.48 mmol), potassiumvinyltrifluoroborate (600 mg, 4.48 mmol), Pd(dppf)Cl₂ (165 mg, 0.224mmol) and CsF (2.04 g, 13.4 mmol) in dioxane/H₂O was stirred at 80° C.for 16 hours. After cooling to room temperature, the mixture waspartitioned between EtOAc and water. The organic layer was washed withwater, brine and dried over Na₂SO₄, concentrated to give the crude whichwas purified by column to give 500 mg of 5-chloro-2-vinylquinazoline asyellow solid. ¹H NMR (CHLOROFORM-d) δ 9.75 (s, 1H), 7.93 (d, J=8.5 Hz,1H), 7.80 (t, J=8.0 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.06 (dd, J=17.2,10.4 Hz, 1H), 6.85 (dd, J=17.3, 1.8 Hz, 1H), 5.90 (dd, J=10.5, 1.5 Hz,1H). LC-MS: m/z 191.0 (M+H).

Building Block 17: 4-chloro-2-vinyl-1,8-naphthyridine

Step 1

A mixture of 25 g of 2-aminonicotinic acid (0.18 mol), 25 g of K₂CO₃(0.18 mol) in 250 mL of DMF was stirred at 140° C. for 30 minutes, thencooled to 10° C. in ice/H₂O, 11 mL of MeI (0.18 mol) was added at 10° C.dropwise, the mixture was stirred at room temperature overnight. Themixture was filtered, the filtrate was concentrated, residue wasdissolved in EtOAc, and filtered again through a pad of silica gel, thefiltrate was concentrated to give 15 g of methyl 2-aminonicotinate. ¹HNMR (400 MHz, CHLOROFORM-d) δ: 7.67 (d, J=7.0 Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.60-7.44 (m, 1H), 3.54 (br. s., 3H).

Step 2

To methyl 2-aminonicotinate (7.48 g, 49 mmol) in EtOAc/THF (150 mL/150mL) was added 13.8 g of KtOBu (123 mmol) in portions slowly at roomtemperature, and the mixture was stirred at room temperature for 50minutes before it was refluxed for 4 hours. After cooling to roomtemperature, the mixture was concentrated, the residue was dissolved in200 mL of H₂O, pH was adjusted to pH=7 with 1N HCl with vigorousstirring, the resulting suspension was filtered, the solid obtained wasdried in vacuum to give 7 g of 1,8-naphthyridine-2,4-diol.

Step 3

A mixture of 8.0 g of 1,8-naphthyridine-2,4-diol (49 mmol) in 80 mL ofPOCl₃ was refluxed for 1.5 hour, excessive POCl₃ was removed underreduced pressure, the residue was poured into satd NaHCO₃ slowly withvigorous stirring, the mixture was extracted with EtOAc, and the organiclayers were dried over Na₂SO₄, concentrated to give 2 g of2,4-dichloro-1,8-naphthyridine, which was used in the subsequentreaction without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ:9.21-9.12 (m, 1H), 8.59 (dd, J=1.8, 8.3 Hz, 1H), 7.67-7.58 (m, 2H).

Step 4

100 mg of 2,4-dichloro-1,8-naphthyridine (0.5 mmol), 68 mg of potassiumvinyltrifluoroborate (0.5 mmol), 130 mg of DIPEA (1 mmol) in iPrOH/H₂O(3 mL/1 mL) was added Pd(dppf)₂Cl₂, then the mixture was stirred at 105°C. in a sealed tube for 1 hour. When TLC (Petroleum ether: Ethylacetate=3:1) indicated the completion of the reaction, the mixture wascooled to room temperature, filtered through a pad of celite, thefiltrate was concentrated to give 120 mg of crude4-chloro-2-vinyl-1,8-naphthyridine, and was used in the subsequentreaction without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ:9.17 (dd, J=1.8, 4.3 Hz, 1H), 8.58 (dd, J=1.9, 8.4 Hz, 1H), 7.62-7.49(m, 2H), 7.13-6.94 (m, 1H), 6.52 (d, J=17.6 Hz, 1H), 5.81 (d, J=10.8 Hz,1H).

Building Block 18: 5-chloro-3-vinylpyridazine

The mixture of 5-chloropyridazin-3-ol (500 mg, 3.36 mmol), potassiumvinyltrifluoroborate (450 mg, 3.36 mmol), Pd(dppf)Cl₂ (124 mg, 0.168mmol) and CsF (1.5 g, 10.07 mmol) in dioxane/H₂O (8 mL/2 mL) was stirredat 100° C. for 16 hours. The mixture was diluted with EtOAc (50 mL) andfiltered. The filtrate was partitioned between EtOAc (50 mL) and water(30 mL), the organic layer was washed with water (30 mL), brine anddried over Na₂SO₄ and concentrated to give the crude which was purifiedby prep-TLC to give 200 mg of the product. ¹H NMR (CHLOROFORM-d) δ 9.06(d, J=2.3 Hz, 1H), 7.60 (d, J=2.3 Hz, 1H), 7.02 (dd, J=17.8, 11.0 Hz,1H), 6.32 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H). LC-MS: m/z 141.0(M+H)⁺

Building Block 19 and 20: tert-butyl 6-chloropyridazin-4-ylcarbamate andtert-butyl 5-chloropyridazin-3-ylcarbamate

The mixture of 3,5-dichloropyridazine (400 mg, 2.68 mmol), BocNH2 (314mg, 2.68 mmol), Pd(dppf)Cl2 (99 mg, 0.134 mmol), Xantphos (155 mg, 0.268mmol) and Cs₂CO₃ (2.61 g, 8.05 mmol) in toluene was stirred at 80° C.for 16 hours. The mixture was diluted with EtOAc (50 mL) and filtered.The filtrate was partitioned between EtOAc (50 mL) and water (30 mL),the organic layer was washed with water (30 mL), brine and dried overNa₂SO₄ and concentrated to give the crude which was purified by prep-TLCto give 150 mg of the product 19 and 120 mg of 20.

tert-butyl 6-chloropyridazin-4-ylcarbamate

¹H NMR (CHLOROFORM-d) δ 8.86 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.3 Hz, 1H),8.12 (br. s., 1H), 1.56 (s, 9H). LC-MS: m/z 230.1 (M+H)⁺

tert-butyl 5-chloropyridazin-3-ylcarbamate

¹H NMR (CHLOROFORM-d) δ 8.94 (s, 1H), 8.04 (s, 1H), 7.37 (br. s., 1H),1.48-1.63 (s, 9H). LC-MS: m/z 230.1 (M+H)⁺

Building Block 21: 4-chloro-6-vinyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.1mmol), potassium vinyl trifluoroborate (13 mg, 0.1 mmol), 5 mgPdCl₂(dppf). CH₂Cl₂ and CsF (45 mg, 0.3 mmol) in dioxane/H₂O (5:1) 3 mLwas stirred at 100° C. for 1 hours. Then the mixture was partitionedbetween EtOAc and water, the organic was washed with water, brine andconcentrated to give the crude which was purified by column to give 14mg of the product. ¹H NMR (CHLOROFORM-d) δ: 11.19 (br. s., 1H), 7.39(br. s., 1H), 7.28 (s, 2H), 6.91 (dd, J=17.3, 10.9 Hz, 1H), 6.62 (br.s., 1H), 6.21 (d, J=17.3 Hz, 1H), 5.55 (d, J=10.9 Hz, 1H). LC-MS: m/z179.6 (M+H)⁺

Building Block 22: 2-vinyl-1,7-naphthyridin-5-yltrifluoromethanesulfonate

Step 1

To a suspension of 5-(4-methoxybenzyloxy)-1,7-naphthyridin-2-ol (180 mg,0.64 mmol) in DMF (5 mL) was added POCl₃ (293 mg, 1.92 mmol). Themixture was heated at 45° C. for 6 h. After cooling to room temperature,the reaction mixture was poured into ice-water, neutralized with NaHCO3,extracted with EtOAc (3×20 mL). The organic layer washed with water (20mL) and brine (20 mL). The solvent was removed and 150 mg crude productwas obtained which was used in next step without further purification.LC-MS: m/z 300 (M+H)⁺

Step 2

To a solution of 2-chloro-5-(4-methoxybenzyloxy)-1,7-naphthyridine (150mg, 0.5 mmol) in EtOH (10 mL) was added 1N HCl (2.5 mL). Then themixture was heated at 90° C. for 2 h. After cooling to room temperature,190 mg of K₂CO₃ was added and followed 10 mL of methanol. The mixturewas stirred vigorously for 1 h at which time silica gel was added. Thesolvent was removed and the residue was purified by columnchromatography (5% methanol/dichloromethane) to give 70 mg of titlecompound (83%). LC-MS: m/z 180 (M+H)⁺

Step 3

A mixture of 2-chloro-1,7-naphthyridin-5-ol (70 mg, 0.39 mmol),Potassium vinyltrifluorobrate (104 mg, 0.78 mmol), Pd(dppf)Cl2 (32 mg,0.039 mmol) and CsF (119 mg, 0.78 mmol) in dioxane:H₂O=5:1 (5 ml+1 ml)was purged with N2 for three times. Then the mixture was heated at 100°C. for 2 h. The solvent was removed and the residue was purified bycolumn chromatography (5% methanol/dichloromethane) to give 30 mg oftitle compound (45%).

LC-MS: m/z 173 (M+H)⁺

Step 4

To a solution of 2-vinyl-1,7-naphthyridin-5-ol (30 mg, 0.17 mmol) andEt3N (35 mg, 0.34 mmol) in dichloromethane (3 mL) was added Tf2O (59 mg,0.21 mmol) at 0° C. Then the temperature was raised to room temperatureand stirred for 2 h. The solvent was removed and the residue waspurified by prep. TLC (EtOAc/petroleum ether=3/7) to give 10 mg of titlecompound (20%). LC-MS: m/z 305 (M+H)⁺

Building Block 23: 4-chloro-1-methyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine

A mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.8 g,4.0 mmol), Potassium vinyltrifluorobrate (540 mg, 4.0 mmol), Pd(dppf)Cl2(98 mg, 0.12 mmol) and CsF (1.22 g, 8 mmol) in dioxane:H2O=5:1 (10 mL+2mL) was purged with N2 three times. Then the mixture was heated at 100°C. for 2 h. The solvent was removed and the residue was purified bycolumn chromatography (30% EtOAc/petroleum ether) to give 500 mg oftitle compound (65%). ¹H NMR (CHLOROFORM-d) δ 8.03 (s, 1H), 7.24 (s,1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.36 (d, J=17.3 Hz, 1H), 5.64 (d,J=10.9 Hz, 1H), 4.16 (s, 3H). LC-MS: m/z 193 (M+H)⁺

Building Block 24: 7-bromo-2-vinylquinoline

Step 1

7-bromoquinoline 1-oxide: to a solution of 7-bromoquinoline (1.04 g, 5mmol) in 20 mL of DCM was added m-Chloroperbenzoic acid (1.01 g, 5 mmol)at room temperature. The reaction mixture was then stirred at roomtemperature overnight. After LC-MS showed the completion of reaction,the mixture was poured into water and extracted with methylene chloride.The combined organic layer was dried over anhy. Na₂SO₄ and concentratedin vacuo. Column chromatography (hexane/ethyl acetate=3/1) afforded 1.0g of title compound as a white solid. LC-MS: m/z 225.1 (M+H)⁺

Step 2

7-bromo-2-chloroquinoline: to a solution of 7-bromoquinoline 1-oxide(1.0 g, 4.5 mmol) in 20 mL of chloroform was added Phosphorusoxychloride (3.42 g, 22 mmol) at room temperature. The reaction mixturewas then heated at reflux for 3 hours. After LC-MS showed the completionof reaction, the mixture was poured into water and extracted withmethylene chloride. The combined organic layer was dried over anhy.Na₂SO₄ and concentrated in vacuo. Column chromatography (hexane/ethylacetate=3/1) afforded 0.75 g of title compound as a white solid. LC-MS:m/z 244.1 (M+H)⁺

Step 3

7-bromo-2-vinylquinoline: to a solution of 7-bromo-2-chloroquinoline(0.75 g, 3 mmol) in 1,4-dioxane (10 mL) was added Potassiumvinyltrifluoroborate (0.42 g, 3 mmol), dichlorobis (triphenylphosphine)palladium (II) (143 mg) and Cesium fluoride (1.40 g, 9 mmol), and themixture was stirred at 100° C. for 10 hours under nitrogen. The mixturewas diluted with ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=4/1) afforded 0.42 g of title compound as awhite solid. LC-MS: m/z 234.9 (M+H)⁺

Building Block 25: (R)-2-(tetrahydrofuran-2-yl)acetic acid

Step 1

(R)-2-(2-(benzyloxy)ethyl)tetrahydrofuran: to a well stirred suspensionof 1.28 g (52 mmol) of NaH in dry diglyme (15 mL) was added 6.86 g (31.2mmol) of trimethylsulfoxonium iodide at room temperature. The mixturewas gently heated to 120° C., and compound 1 (Step 4 product in buildingblock 6 scheme) (1 g, 5.2 mmol) in diglyme (3 mL) was added in oneportion. The reaction mixture was stirred at 120° for 4 hours, cooled,carefully quenched with water, and extracted three times with n-hexane.The combined extracts were washed with water and brine and dried overNa2SO4. Removal of solvent and purification by chromatography on silicagel gave the compound 2 (0.5 g, 46%). ¹H NMR (CHLOROFORM-d) δ 7.34-7.42(m, 4H), 7.26-7.34 (m, 1H), 4.43-4.63 (m, 2H), 3.91-4.05 (m, 1H),3.83-3.91 (m, 1H), 3.74 (td, J=7.9, 6.5 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H),1.96-2.05 (m, 1H), 1.73-1.95 (m, 4H), 1.52 (dd, J=11.9, 8.7 Hz, 1H).

Step 2

(R)-2-(tetrahydrofuran-2-yl)ethanol: to a solution of compound 2 (0.3 g,1.45 mmol) in MeOH (15 mL) was added 10% Pd(OH)₂/C (20 mg). The reactionmixture was purged with hydrogen and stirred under an atmosphere ofhydrogen for 2 d. The black suspension was passed through a plug ofcelite eluting with MeOH, then the solution was concentrated to yieldthe desired product as colorless oil (0.15 g, 89%). ¹H NMR(CHLOROFORM-d, 400 MHz): δ 4.00-4.08 (m, 1H), 3.86-4.00 (m, 1H),3.66-3.86 (m, 3H), 2.87 (br. s., 1H), 1.98-2.10 (m, 1H), 1.84-1.98 (m,2H), 1.70-1.84 (m, 2H), 1.46-1.63 ppm (m, 1H).

Step 3

(R)-2-(tetrahydrofuran-2-yl)acetic acid: to a mixture of compound 3(0.15 g, 1.3 mmol), sodium periodate (0.72 G, 2.6 mmol), water (10 mL),acetonitrile (20 mL) and carbon tetrachloride (20 mL) was addedruthenium trichloride (29 mg, 10 mol %) at 0-5° C. Afterwards, theresulting mixture was allowed to warm to rt and stirred at thistemperature for 2 h. The precipitate was removed via filtration througha pad of celite and washed with diethylether (around 100 mL×5). Thecombined organic phase was washed with brine (50 mL×3) and then driedunder reduced pressure to get the compound 4 (60 mg, contain about 8% ofthe byproduct). ¹H NMR (CHLOROFORM-d, 400 MHz): δ 4.19-4.33 (m, 1H),3.89-4.06 (m, 1H), 3.83 (td, J=7.8, 6.5 Hz, 1H), 2.62 (dd, J=6.5, 1.5Hz, 2H), 2.07-2.23 (m, 1H), 1.89-2.06 (m, 2H), 1.54-1.72 (m, 1H).

Example 16 The Following Compounds were Made Following Methods Analogousto Those for Compound 273(R)-5-(2-cyanophenyl)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile(Compound 274; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.76-7.82 (m, 1H), 7.69 (td, J=7.7, 1.4 Hz, 1H),7.58-7.63 (m, 1H), 7.52 (td, J=7.7, 1.1 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H),4.56-4.79 (m, 1.5H), 4.44 (t, J=10.3 Hz, 1.5H), 3.86 (d, J=13.8 Hz,0.5H), 3.70-3.79 (m, 2H), 3.51-3.65 (m, 0.5H), 3.34-3.49 (m, 3.5H),3.03-3.24 (m, 2H), 2.87-3.00 (m, 0.5H), 2.53-2.82 (m, 2H), 2.05-2.29 (m,1H), 1.63-1.77 (m, 1H), 1.26 (br. s., 1H), 0.93-1.23 (m, 7H), 0.87-0.92(m, 1.5H), 0.84 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 458.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-methoxyphenyl)nicotinonitrile(Compound 275; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.58 (d, J=2.5 Hz, 1H), 7.39 (td, J=7.9, 1.8 Hz,1H), 7.18-7.25 (m, 1H), 7.04 (td, J=7.4, 1.0 Hz, 1H), 6.99 (d, J=8.0 Hz,1H), 4.69 (d, J=12.8 Hz, 0.5H), 4.49-4.60 (m, 1H), 4.44 (d, J=10.5 Hz,0.5H), 4.25-4.38 (m, 1H), 3.79-3.89 (m, 4H), 3.68-3.78 (m, 2H),3.51-3.63 (m, 0.5H), 3.34-3.42 (m, 3H), 2.90-3.16 (m, 2.5H), 2.53-2.82(m, 2H), 2.09-2.36 (m, 1H), 1.75-1.88 (m, 1H), 1.02-1.18 (m, 5H),0.79-0.96 (m, 5H). LC-MS: m/z 463.2 (M+H)⁺

COMPOUND AGI-0007758/NB162-086 (General Procedure 1, Step H)(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-(trifluoromethoxy)phenyl)nicotinonitrile(Compound 276; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.54 (d, J=2.0 Hz, 1H), 7.43-7.48 (m, 1H),7.33-7.41 (m, 3H), 4.69 (d, J=13.3 Hz, 0.5H), 4.60 (t, J=13.3 Hz, 1H),4.41 (dd, J=16.8, 13.3 Hz, 1.5H), 3.85 (d, J=13.3 Hz, 0.5H), 3.70-3.79(m, 2H), 3.52-3.62 (m, 0.5H), 3.35-3.49 (m, 3.5H), 3.03-3.23 (m, 2H),2.89-3.02 (m, 0.5H), 2.53-2.82 (m, 2H), 1.67-1.78 (m, 1H), 1.04-1.12 (m,5H), 0.77-0.98 (m, 6H). LC-MS: m/z 517.2 (M+H)⁺

(R)-1-(4-(6-cyclopropyl-5-(4-fluorophenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)-2-methylpiperazin-1-yl)-3-methoxypropan-1-one(Compound 831)

To a solution of N′-hydroxyacetimidamide (221 mg, 2 mmol) hydrochloridein 10 mL anhydrous THF was added NaH (48 mg, 2 mmol). The reactionmixture was heated reflux for 0.5 h and (R)-methyl6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinate(455 mg, 1 mmol) was added to this solution. The reaction was continuedreflux for 2 h. The reaction was cooled down to RT and filtered. Thefiltrate was concentrated to dryness and 120 mg product was obtained byprep-TLC. ¹H NMR (CHLOROFORM-d) δ 7.99 (s, 1H), 7.33-7.49 (m, 2H),7.05-7.23 (m, 2H), 4.85 (br. s., 0.5H), 4.42 (d, J=13.1 Hz, 0.5H), 4.17(br. s., 0.5H), 3.77-3.93 (m, 2H), 3.47-3.77 (m, 6H), 3.37 (s, 4H),3.06-3.26 (m, 2H), 2.81-3.06 (m, 1H), 2.51-2.80 (m, 3H), 2.31-2.49 (m,3H), 1.87-2.11 (m, 1H), 1.28-1.43 (m, 1.5H), 1.15-1.28 (m, 3.5H), 1.12(br. s., 1H), 0.80-1.06 (m, 2H).

(R)-5-(3-cyanophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 283; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.66-7.71 (m, 2H), 7.62-7.65 (m, 1H), 7.55-7.60(m, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.18-4.40 (m,2.5H), 3.67-3.88 (m, 2.5H), 3.46-3.62 (m, 0.5H), 3.38 (s, 3H), 3.24-3.35(m, 1H), 2.99-3.20 (m, 1.5H), 2.64-2.81 (m, 1H), 2.49-2.63 (m, 1H),1.85-1.97 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.5 Hz, 1.5H),1.14-1.21 (m, 2H), 0.94-1.04 (m, 2H). LC-MS: m/z 430.2 (M+H)⁺

(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 285; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.57-7.60 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 6.77(d, J=7.8 Hz, 1H), 6.68-6.74 (m, 2H), 4.89 (br. s., 0.5H), 4.52 (d,J=13.3 Hz, 0.5H), 4.09-4.31 (m, 2.5H), 3.67-3.81 (m, 2.5H), 3.47-3.60(m, 0.5H), 3.37 (s, 3H), 3.18-3.29 (m, 1H), 2.95-3.16 (m, 1.5H),2.63-2.78 (m, 1H), 2.52-2.61 (m, 1H), 2.09-2.17 (m, 1H), 1.38 (d, J=6.5Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.06-1.16 (m, 2H), 0.88-0.99 (m,2H). LC-MS: m/z 420.1 (M+H)⁺

(R)-6-cyclopropyl-5-(isoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 286; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.34 (s, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.06 (d,J=8.0 Hz, 1H), 7.68-7.75 (m, 1H), 7.61-7.68 (m, 2H), 7.43 (t, J=5.6 Hz,1H), 4.94 (br. s., 0.5H), 4.57 (d, J=13.1 Hz, 0.5H), 4.18-4.47 (m,2.5H), 3.69-3.86 (m, 2.5H), 3.54-3.67 (m, 0.5H), 3.37-3.44 (m, 3H), 3.34(dd, J=13.1, 6.3 Hz, 1H), 3.04-3.25 (m, 1.5H), 2.67-2.78 (m, 1H),2.54-2.67 (m, 1H), 1.48-1.58 (m, 1H), 1.39-1.47 (m, 1.5H), 1.29-1.39 (m,1.5H), 1.09-1.21 (m, 2H), 0.75-0.89 (m, 2H). LC-MS: m/z 456.1 (M+H)⁺

(R)-6-cyclopropyl-5-(1H-indol-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 287; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.40 (br. s., 1H), 7.74 (s, 1H), 7.44 (d, J=8.3Hz, 1H), 7.24-7.29 (m, 1H), 7.02-7.10 (m, 1H), 6.37-6.45 (m, 1H), 4.92(br. s., 0.5H), 4.55 (d, J=13.6 Hz, 0.5H), 4.17-4.39 (m, 2.5H),3.71-3.86 (m, 2.5H), 3.51-3.65 (m, 0.5H), 3.35-3.44 (m, 3H), 3.20-3.32(m, 1H), 2.98-3.17 (m, 1.5H), 2.66-2.81 (m, 1H), 2.54-2.64 (m, 1H),1.94-2.04 (m, 1H), 1.40-1.46 (m, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H),1.08-1.17 (m, 2H), 0.80-0.91 (m, 2H). LC-MS: m/z 444.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(quinolin-5-yl)nicotinonitrile(Compound 288; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.97 (dd, J=4.1, 1.6 Hz, 1H), 8.23 (d, J=8.5 Hz,1H), 7.94-8.05 (m, 1H), 7.82 (dd, J=8.5, 7.0 Hz, 1H), 7.61-7.66 (m, 1H),7.48-7.55 (m, 1H), 7.40-7.48 (m, 1H), 4.83-5.06 (m, 0.5H), 4.56 (d,J=13.1 Hz, 0.5H), 4.15-4.43 (m, 2.5H), 3.69-3.91 (m, 2.5H), 0.57 (d,J=10.5 Hz, 0.5H), 3.36-3.45 (m, 3H), 3.33 (dd, J=13.1, 3.5 Hz, 1H),3.01-3.26 (m, 1.5H), 2.65-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.48-1.56 (m,1H), 1.39-1.47 (m, 1.5H), 1.29-1.38 (m, 1.5H), 1.07-1.18 (m, 2H),0.74-0.91 (m, 2H). LC-MS: m/z 456.1 (M+H)⁺

(R)-6-cyclopropyl-5-(1H-indol-6-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 289; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.41 (br. s., 1H), 7.69 (d, J=8.0 Hz, 1H), 7.66(s, 1H), 7.39 (s, 1H), 7.27-7.30 (m, 1H), 7.13 (dd, J=8.0, 1.5 Hz, 1H),6.60 (t, J=2.1 Hz, 1H), 4.91 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H),4.13-4.32 (m, 2.5H), 3.68-3.84 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s,3H), 3.17-3.31 (m, 1H), 2.93-3.16 (m, 1.5H), 2.64-2.82 (m, 1H),2.53-2.63 (m, 1H), 2.13-2.23 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d,J=6.8 Hz, 1.5H), 1.09-1.17 (m, 2H), 0.84-0.98 (m, 2H).

LC-MS: m/z 444.2 (M+H)⁺

(R)-6-cyclopropyl-5-(4-fluoronaphthalen-1-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 290; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.19 (d, J=8.0 Hz, 1H), 7.50-7.65 (m, 4H),7.30-7.37 (m, 1H), 7.22 (dd, J=10.2, 7.9 Hz, 1H), 4.93 (br. s., 0.5H),4.56 (d, J=13.3 Hz, 0.5H), 4.15-4.42 (m, 2.5H), 3.69-3.90 (m, 2.5H),3.50-3.68 (m, 0.5H), 3.36-3.43 (m, 3H), 3.24-3.34 (m, 1H), 3.00-3.23 (m,1.5H), 2.65-2.85 (m, 1H), 2.55-2.64 (m, 1H), 1.54-1.61 (m, 1H),1.40-1.48 (m, 1.5H), 1.33 (dd, J=6.3, 3.5 Hz, 1.5H), 1.07-1.18 (m, 2H),0.72-0.85 (m, 2H). LC-MS: m/z 473.1 (M+H)⁺

(R)-methyl2-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)acetate(Compound 291; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.36-7.45 (m, 1H), 7.25-7.34 (m,3H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H), 4.26 (t, J=12.5 Hz,2.5H), 3.64-3.85 (m, 7H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H), 3.19-3.30(m, 1H), 2.93-3.18 (m, 2H), 2.63-2.81 (m, 1H), 2.49-2.63 (m, 1H),2.02-2.12 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H),1.10-1.20 (m, 2H), 0.89-1.00 (m, 2H). LC-MS: m/z 477.1 (M+H)⁺

(R)-6-cyclopropyl-5-(1H-indazol-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 295; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 8.14 (br. s., 1H), 7.75 (s, 1H), 7.65 (s, 1H),7.59 (d, J=8.5 Hz, 1H), 7.42 (dd, J=8.7, 1.4 Hz, 1H), 4.91 (br. s.,0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.12-4.39 (m, 2.5H), 3.69-3.89 (m,2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.20-3.33 (m, 1H), 2.97-3.20(m, 1.5H), 2.66-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.99-2.14 (m, 1H),1.36-1.46 (m, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.13-1.21 (m, 2H),0.90-0.99 (m, 2H). LC-MS: m/z 445.4 (M+H)⁺

(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)benzamide(Compound 296; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.84-7.96 (m, J=8.5 Hz, 2H), 7.57-7.66 (m, 1H),7.45-7.56 (m, 2H), 6.27 (br. s., 1H), 5.99 (br. s., 1H), 4.90 (br. s.,0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.14-4.38 (m, 2.5H), 3.70-3.87 (m,2.5H), 3.47-3.62 (m, 0.5H), 3.33-3.43 (m, 3H), 3.27 (t, J=10.3 Hz, 1H),2.99-3.21 (m, 1.5H), 2.64-2.83 (m, 1H), 2.50-2.64 (m, 1H), 1.95-2.09 (m,1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.25-1.31 (m, 1.5H), 1.13-1.21 (m, 2H),0.92-1.02 (m, 2H). LC-MS: m/z 448.5 (M+H)⁺

(R)-6-cyclopropyl-5-(3-(2-hydroxyethyl)phenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 297; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.35-7.42 (m, 1H), 7.23-7.27 (m,3H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.14-4.31 (m,2.5H), 3.91 (t, J=6.7 Hz, 2H), 3.68-3.83 (m, 2.5H), 3.49-3.61 (m, 0.5H),3.37 (s, 3H), 3.19-3.29 (m, 1H), 2.97-3.18 (m, 1.5H), 2.91-2.97 (m, 2H),2.64-2.81 (m, 1H), 2.52-2.62 (m, 1H), 2.02-2.14 (m, 1H), 1.39 (d, J=6.3Hz, 1.5H), 1.27-1.32 (m, 1.5H), 1.08-1.19 (m, 2H), 0.89-1.02 (m, 2H).LC-MS: m/z 449.6 (M+H)⁺

(R)-3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)benzamide(Compound 305; General procedure 1, Step H)

¹H NMR (METHANOL-d₄) δ 7.96 (t, J=1.5 Hz, 1H), 7.91 (dt, J=7.7, 1.6 Hz,1H), 7.81 (s, 1H), 7.62-7.67 (m, 1H), 7.56-7.62 (m, 1H), 4.82 (br. s.,0.5H), 4.38-4.48 (m, 1H), 4.16-4.29 (m, 2H), 3.97 (d, J=13.6 Hz, 0.5H),3.68-3.76 (m, 2H), 3.54-3.67 (m, 0.5H), 3.36 (s, 4H), 3.05-3.26 (m,1.5H), 2.72-2.89 (m, 1H), 2.57-2.70 (m, 1H), 1.99-2.10 (m, 1H), 1.40 (d,J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 1.20 (dq, J=4.4, 3.1 Hz, 2H),0.93-1.04 (m, 2H). LC-MS: m/z 448.3 (M+H)⁺

(R)-6-cyclopropyl-5-(3-(hydroxymethyl)phenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 306; General procedure 1, Step H)

¹H NMR (METHANOL-d₄) δ 7.71 (br. s., 1H), 7.37-7.48 (m, 3H), 7.32 (d,J=7.5 Hz, 1H), 4.80 (br. s., 1H), 4.68 (s, 3H), 4.36-4.51 (m, 1H),4.13-4.30 (m, 2H), 3.95 (d, J=13.6 Hz, 0.5H), 3.67-3.78 (m, 2H),3.50-3.65 (m, 0.5H), 3.27-3.35 (m, 2.5H), 2.99-3.20 (m, 1.5H), 2.70-2.84(m, 1H), 2.61-2.67 (m, 1H), 2.06-2.13 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H),1.28 (d, J=6.8 Hz, 1.5H), 1.12-1.24 (m, 2H), 0.96 (dd, J=7.3, 3.5 Hz,2H). LC-MS: m/z 435.3 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-oxoindolin-6-yl)nicotinonitrile(Compound 313; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.40 (s, 1H), 7.53-7.64 (m, 1H), 7.29 (d, J=7.8Hz, 1H), 6.98-7.07 (m, 1H), 6.87-6.93 (m, 1H), 4.90 (br. s., 0.5H), 4.53(d, J=13.4 Hz, 0.5H), 4.13-4.37 (m, 2.5H), 3.68-3.88 (m, 2.5H),3.49-3.65 (m, 2.5H), 3.34-3.43 (m, 3H), 3.20-3.31 (m, 1H), 2.95-3.18 (m,1.5H), 2.51-2.81 (m, 2H), 2.02-2.15 (m, 1H), 1.38-1.40 (m, 1.5H),1.26-1.31 (m, 1.5H), 1.07-1.20 (m, 2H), 0.90-1.04 (m, 2H). LC-MS: m/z460.2 (M+H)⁺

(R)-6′-amino-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,3′-bipyridine-5-carbonitrile(Compound 314; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.10 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.44-7.50(m, 1H), 6.55-6.64 (m, 1H), 4.89 (br. s., 0.5H), 4.72 (br. s., 2H), 4.52(d, J=13.3 Hz, 0.5H), 4.15-4.31 (m, 2.5H), 3.69-3.85 (m, 2.5H),3.49-3.63 (m, 0.5H), 3.34-3.43 (m, 3H), 3.19-3.31 (m, 1H), 2.96-3.17 (m,1.5H), 2.51-2.81 (m, 2H), 1.99-2.08 (m, 1H), 1.23-1.41 (m, 3H),1.11-1.18 (m, 2H), 0.90-0.99 (m, 2H). LC-MS: m/z 421.4 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(quinolin-4-yl)nicotinonitrile(Compound 315; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.99 (d, J=4.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H),7.78 (t, J=7.5 Hz, 1H), 7.61-7.71 (m, 2H), 7.53-7.61 (m, 1H), 7.36 (d,J=4.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=12.5 Hz, 0.5H), 4.25-4.45(m, 2.5H), 3.68-3.91 (m, 2.5H), 3.57 (d, J=9.3 Hz, 0.5H), 3.29-3.45 (m,4H), 3.01-3.27 (m, 1.5H), 2.65-2.84 (m, 1H), 2.51-2.65 (m, 1H), 1.54(td, J=8.2, 4.1 Hz, 1H), 1.42 (d, J=5.5 Hz, 1.5H), 1.32 (t, J=5.0 Hz,1.5H), 1.05-1.21 (m, 2H), 0.74-0.92 (m, 2H). LC-MS: m/z 456.0 (M+H)⁺

(R)-6-cyclopropyl-5-(2,6-dimethoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 316; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.51-7.57 (m, 1H), 7.30-7.38 (m, 1H), 6.65 (d,J=8.3 Hz, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.11-4.34(m, 2.5H), 3.67-3.84 (m, 8.5H), 3.47-3.62 (m, 0.5H), 3.32-3.43 (m, 3H),2.95-3.24 (m, 2.5H), 2.63-2.84 (m, 1H), 2.51-2.63 (m, 1H), 1.65-1.72 (m,1H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.00-1.12 (m,2H), 0.75-0.86 (m, 2H). LC-MS: m/z 465.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(2,2,2-trifluoroacetyl)-1H-indol-5-yl)nicotinonitrile(Compound 317; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.44 (s, 1H), 8.10-8.18 (m, 1H), 7.67 (s, 1H),7.56 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 4.92 (br. s., 0.5H),4.55 (d, J=12.8 Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.69-3.88 (m, 2.5H),3.52-3.69 (m, 0.5H), 3.35-3.45 (m, 3H), 3.22-3.35 (m, 1H), 0.98-3.20 (m,1.5H), 2.54-2.82 (m, 2H), 2.04-2.13 (m, 1H), 1.38-1.47 (m, 1.5H), 1.31(d, J=6.5 Hz, 1.5H), 1.14-1.19 (m, 2H), 0.90-0.97 (m, 2H). LC-MS: m/z540.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(quinolin-8-yl)nicotinonitrile(Compound 342; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.94 (dd, J=4.1, 1.6 Hz, 1H), 8.23 (dd, J=8.3,1.8 Hz, 1H), 7.90 (dd, J=8.2, 1.4 Hz, 1H), 7.73 (s, 1H), 7.66-7.71 (m,1H), 7.59-7.66 (m, 1H), 7.45 (dd, J=8.3, 4.3 Hz, 1H), 4.92 (br. s.,0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.13-4.38 (m, 2.5H), 3.68-3.87 (m,2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.24 (t, J=12.8 Hz, 1H),2.96-3.17 (m, 1.5H), 2.52-2.82 (m, 2H), 1.59-1.68 (m, 1H), 1.43 (d,J=6.5 Hz, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 1.07 (br. s., 2H), 0.78 (br.s., 2H)

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)acetamide(Compound 284; General procedure 3, step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.58 (s, 2H), 7.46 (d, J=8.0 Hz,1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.89 (br. s.,0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.11-4.36 (m, 2.5H), 3.67-3.86 (m,2.5H), 3.54 (t, J=10.9 Hz, 0.5H), 3.33-3.43 (m, 3H), 3.18-3.31 (m, 1H),2.94-3.17 (m, 1.5H), 2.63-2.79 (m, 1H), 2.51-2.63 (m, 1H), 2.17-2.28 (m,3H), 2.06-2.14 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=7.0 Hz,1.5H), 1.08-1.17 (m, 2H), 0.91-1.00 (m, 2H). LC-MS: m/z 462.2 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)acrylamide(Compound 343; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.70-7.79 (m, 2H), 7.54-7.63 (m, 2H), 7.41 (t,J=7.9 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.48 (dd, J=16.8, 1.0 Hz, 1H),6.31 (dd, J=16.8, 10.0 Hz, 1H), 5.81 (dd, J=10.2, 1.1 Hz, 1H), 4.91 (br.s., 1H), 4.54 (d, J=13.1 Hz, 0.5H), 4.12-4.36 (m, 2.5H), 3.69-3.88 (m,2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3H), 3.20-3.33 (m, 1H), 2.96-3.17(m, 1.5H), 2.54-2.81 (m, 2H), 2.07-2.16 (m, 1H), 1.39 (d, J=6.5 Hz,1.5H), 1.25-1.35 (m, 1.5H), 1.15 (quin, J=3.6 Hz, 2H), 0.89-1.02 (m,2H). LC-MS: m/z 474.6 (M+H)⁺(R,E)-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)but-2-enamide(Compound 415; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 7.64-7.76 (m, 2H), 7.60-7.63 (m, 1H), 7.49-7.53(m, 1H), 7.37-7.44 (m, 1H), 7.30-7.35 (m, 1H), 7.14 (d, J=7.8 Hz, 1H),6.95-7.10 (m, 1H), 5.99 (dd, J=15.1, 1.8 Hz, 1H), 4.92 (s, 0.5H), 4.54(d, J=12.8 Hz, 0.5H), 4.20-4.32 (m, 2.5H), 3.76 (t, J=6.3 Hz, 2H),3.50-3.62 (m, 0.5H), 3.39 (s, 3H), 3.18-3.34 (m, 1.5H), 2.97-3.16 (m,1.5H), 2.65-2.80 (m, 1H), 2.53-2.65 (m, 1H), 2.09-2.16 (m, 1H), 1.95(dd, J=6.8, 1.5 Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 1.29-1.31 (m, 2H),1.12-1.19 (m, 2H), 0.92-1.01 (m, 2H)

LC-MS: m/z 487.3 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)-2-oxopropanamide(Compound 416; General procedure 3, step N, method 2)

¹H NMR (CHLOROFORM-d) δ 7.38-7.66 (m, 4H), 7.32 (dd, J=3.9, 1.9 Hz, 1H),7.12-7.25 (m, 1H), 4.89 (s, 0.5H), 4.52 (d, J=10.8 Hz, 0.5H), 4.22-4.34(m, 2H), 4.10-4.22 (m, 0.5H), 3.66-3.85 (m, 2.5H), 3.55 (d, J=3.5 Hz,0.5H), 3.39 (d, J=1.5 Hz, 3H), 3.20-3.31 (m, 1H), 3.10-3.14 (m, 1.5H),2.97-3.09 (m, 1H), 2.66-2.80 (m, 1H), 2.53-2.64 (m, 1H), 1.97-2.07 (m,1H), 1.55-1.58 (m, 3H), 1.35-1.42 (m, 2H), 1.10-1.17 (m, 1H), 1.05-1.10(m, 1H), 0.73-0.96 (m, 4H). LC-MS: m/z 490.2 (M+H)⁺

(R)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)acetamide(Compound 403; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 8.34 (s, 1H), 7.66-7.75 (m, 1H), 7.62 (s, 1H),7.50-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.22 (d, J=7.8 Hz, 1H), 4.92 (s,0.5H), 4.50-4.54 (m, 0.5H), 4.29-4.33 (m, 1H), 4.26 (m, 1H), 4.21-4.25(m, 0.5H), 3.71-3.84 (m, 2.5H), 3.52-3.57 (m, 0.5H), 3.39 (s, 3H),3.21-3.32 (m, 1H), 3.13 (d, J=11.3 Hz, 1H), 3.05 (d, J=12.3 Hz, 0.5H),2.66-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.07-2.12 (m, 1H), 1.40 (d, J=6.3Hz, 1H), 1.28-1.31 (m, 2H), 1.14-1.19 (m, 2H), 0.94-1.00 (m, 2H). LC-MS:m/z 495.2 (M+H)⁺

(R)-1-chloro-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)methanesulfonamide(Compound 404; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.44-7.52 (m, 1H), 7.36-7.41 (m,1H), 7.29-7.36 (m, 2H), 7.11 (br. s., 1H), 4.92 (s, 1H), 4.45-4.63 (m,2.5H), 4.18-4.40 (m, 2.5H), 3.66-3.89 (m, 2.5H), 3.50-3.57 (m, 0.5H),3.39 (s, 3H), 3.29 (t, J=10.2 Hz, 1H), 2.99-3.20 (m, 1.5H), 2.65-2.83(m, 1H), 2.52-2.64 (m, 1H), 1.99-2.06 (m, 1H), 1.40 (d, J=6.3 Hz, 1H),1.30 (s, 2H), 1.15-1.22 (m, 2H), 0.96-1.03 (m, 2H). LC-MS: m/z 531.2(M+H)⁺

(R)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)propanamide(Compound 462; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 8.54 (s, 1H), 7.67-7.73 (m, 1H), 7.60 (s, 1H),7.49-7.57 (m, 1H), 7.38-7.45 (m, 1H), 7.14-7.22 (m, 1H), 4.90 (br. s.,0.5H), 4.44-4.64 (m, 1.5H), 4.16-4.37 (m, 2.5H), 3.68-3.86 (m, 2.5H),3.50-3.63 (m, 0.5H), 3.37 (s, 3H), 3.19-3.32 (m, 1H), 2.96-3.17 (m,1.5H), 2.53-2.78 (m, 2H), 2.05-2.12 (m, 1H), 1.83 (d, J=7.0 Hz, 3H),1.39 (d, J=6.5 Hz, 1.5H), 1.28 (dd, J=6.9, 2.6 Hz, 1.5H), 1.10-1.19 (m,2H), 0.90-1.02 (m, 2H). LC-MS: m/z 510.2 (M+H)⁺

(R)—N-(4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)acetamide(Compound 412; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.55-7.67 (m, 3H), 7.31-7.44 (m, 3H), 4.91 (s,0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.14-4.33 (m, 2.5H), 3.65-3.93 (m,2.5H), 3.46-3.65 (m, 0.5H), 3.39 (s, 3H), 3.20-3.30 (m, 1H), 2.98-3.19(m, 1.5H), 2.51-2.81 (m, 1H), 2.16-2.31 (m, 3H), 1.98-2.13 (m, 1H),1.24-1.44 (m, 4H), 1.08-1.18 (m, 2H), 0.84-0.99 (m, 2H). LC-MS: m/z462.6 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)propionamide(Compound 424; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.49(d, J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 4.89(s, 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.14-4.35 (m, 2.5H), 3.67-3.85 (m,2.5H), 3.49-3.62 (m, 0.5H), 3.37 (s, 3H), 3.17-3.32 (m, 1H), 2.93-3.17(m, 1.5H), 2.63-2.81 (m, 1H), 2.52-2.63 (m, 1H), 2.37-2.49 (m, 2H),2.05-2.13 (m, 1H), 1.38 (d, J=6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1.14 (dt,J=7.4, 3.6 Hz, 2H), 0.88-1.01 (m, 2H). LC-MS: m/z 476.3 (M+H)⁺

(R)-1-cyano-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)cyclopropanecarboxamide(Compound 425; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 8.11 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H),7.42-7.50 (m, 2H), 7.19-7.25 (m, 1H), 4.92 (s, 0.5H), 4.55 (d, J=12.3Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.71-3.76 (m, 2.5H), 3.55-3.58 (m,0.5H), 3.36-3.46 (m, 3H), 3.21-3.33 (m, 1H), 3.14 (d, J=13.3 Hz, 1.5H),3.05 (d, J=12.0 Hz, 1H), 2.63-3.75 (s, 1H), 2.61-3.63 (m, 1H), 2.02-2.12(m, 1H), 1.81-1.91 (m, 2H), 1.66 (q, J=4.5 Hz, 2H), 1.40 (d, J=5.5 Hz,1H), 1.25-1.33 (m, 2H), 1.12-1.20 (m, 2H), 0.92-1.01 (m, 2H). LC-MS: m/z513.2 (M+H)⁺

Compound 427 (General Procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.62 (s, 1H), 7.47-7.56 (m, 1H), 7.35-7.44 (m,1H), 7.18-7.25 (m, 2H), 6.42 (dd, J=16.8, 2.0 Hz, 1H), 6.16 (dd, J=16.6,10.3 Hz, 1H), 5.57 (dd, J=10.2, 1.6 Hz, 1H), 4.92 (d, J=12.8 Hz, 0.5H),4.55 (d, J=12.8 Hz, 0.5H), 4.13-4.41 (m, 3H), 3.69-3.90 (m, 3H), 3.58(d, J=9.3 Hz, 1H), 3.39 (s, 3H), 3.42 (s, 3H), 3.29 (t, J=9.5 Hz, 1H),3.01-3.21 (m, 2H), 2.65-2.80 (m, 1H), 2.47-2.65 (m, 1H), 1.88-2.07 (m,1H), 1.65 (br. s., 3H), 1.35-1.44 (m, 2H), 1.25-1.35 (m, 2H), 1.09-1.25(m, 2H), 0.92-1.09 (m, 2H). LC-MS: m/z 488.2 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)propiolamide(Compound 428; General procedure 3, Step N, Method 2)

¹H NMR (CHLOROFORM-d) δ 7.63-7.69 (m, 2H), 7.61 (s, 1H), 7.41-7.50 (m,2H), 7.20 (d, J=7.3 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=11.8 Hz, 0.5H),4.12-4.40 (m, 2.5H), 3.72-3.79 (m, 2.5H), 3.51-3.57 (m, 0.5H), 3.40 (s,3H), 3.23-3.32 (m, 1H), 3.14 (d, J=13.1 Hz, 1H), 3.05 (d, J=11.0 Hz,1H), 2.99 (s, 1H), 2.65-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.05-2.13 (m,1H), 1.40 (d, J=6.5 Hz, 1H), 1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H),0.88-0.93 (m, 2H).

LC-MS: m/z 472.2 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)ethenesulfonamide(Compound 429; General procedure 3, Step N, method 1)

To a solution of(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(20 mg, 0.048 mmol) and 2-chloroethanesulfonyl chloride (8.6 mg, 0.052mmol) in 5 ml of DCM was added dropwised TEA (15 mg, 0.143 mmol) at 0°C., then the resulting mixture was allowed to warm to room temperatureand stirred for 2 hours. The mixture was partitioned between EtOAc andwater. The organic layer was dried over Na₂SO₄ and concentrated to givethe crude which was purified by prep-TLC to give 15 mg of the product.¹H NMR (CHLOROFORM-d) δ 7.55-7.61 (m, 1H), 7.37-7.46 (m, 1H), 7.15-7.26(m, 3H), 6.70 (d, J=12.8 Hz, 1H), 6.62 (dd, J=16.4, 9.9 Hz, 1H), 6.34(d, J=16.3 Hz, 1H), 6.02 (d, J=9.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d,J=13.3 Hz, 0.5H), 4.19-4.37 (m, 2.5H), 3.73-3.79 (m, 3H), 3.52-3.61 (m,0.5H), 3.39 (s, 3H), 3.28 (t, J=10.4 Hz, 1H), 3.02-3.14 (m, 1H),2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 1.98-2.07 (m, 1H), 1.27 (s, 3H),1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H).

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)-2-fluoroacrylamide(Compound 431; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 8.19 (d, J=4.5 Hz, 1H), 7.75 (s, 1H), 7.61 (s,1H), 7.57 (dd, J=8.0, 1.3 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.16-7.23 (m,1H), 5.84 (dd, J=18.0 Hz, J=3.3 Hz, 0.5H), 5.21-5.35 (m, 1H), 4.90 (br.s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.10-4.38 (m, 2.5H), 3.66-3.86 (m,2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.19-3.33 (m, 1H), 2.95-3.18(m, 1.5H), 2.56-2.78 (m, 2H), 2.04-2.16 (m, 1H), 1.39 (d, J=6.3 Hz,1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.11-1.22 (m, 2H), 0.91-1.03 (m, 2H).LC-MS: m/z 492.7 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)-2,2-difluoroacetamide(Compound 432; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 8.79 (br. s., 1H), 7.77 (s, 1H), 7.55-7.65 (m,2H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 6.05 (t, J=56.0 Hz,1H), 4.89 (br. s., 0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.08-4.37 (m,2.5H), 3.66-3.88 (m, 2.5H), 3.49-3.63 (m, 0.5H), 3.36 (s, 3H), 2.96-3.25(m, 2.5H), 2.81 (s, 6H), 2.50-2.79 (m, 2H), 2.03-2.13 (m, 1H), 1.32-1.45(m, 1.5H), 1.27 (d, J=6.8 Hz, 1.5H), 1.10-1.17 (m, 2H), 0.91-1.02 (m,2H)

LC-MS: m/z 498.8 (M+H)⁺

(R)-5-(4-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 383; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.53-7.62 (m, 1H), 7.11-7.21 (m, 2H), 6.70-6.83(m, 2H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.04-4.28 (m,2.5H), 3.64-3.88 (m, 4.5H), 3.47-3.64 (m, 0.5H), 3.30-3.43 (m, 3H),3.14-3.27 (m, 1H), 2.92-3.14 (m, 1.5H), 2.50-2.79 (m, 2H), 2.08-2.15 (m,1H), 1.34-1.43 (m, 1.5H), 1.28-1.30 (m, 1.5H), 1.06-1.15 (m, 2H),0.84-0.95 (m, 2H). LC-MS: m/z 420.1 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-oxoindolin-5-yl)nicotinonitrile(Compound 384; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.22 (s, 1H), 7.50-7.64 (m, 1H), 7.21-7.26 (m,2H), 6.85-7.03 (m, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H),4.10-4.37 (m, 2.5H), 3.68-3.86 (m, 2.5H), 3.48-3.64 (m, 2.5H), 3.35-3.44(m, 3H), 3.19-3.31 (m, 1H), 2.94-3.17 (m, 1.5H), 2.52-2.82 (m, 2H),1.99-2.09 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H),1.09-1.20 (m, 2H), 0.91-0.99 (m, 2H). LC-MS: m/z 460.5 (M+H)⁺

(R)-6-cyclopropyl-5-(1H-indazol-6-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 385; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.14 (br. s., 1H), 7.82 (d, J=8.3 Hz, 1H), 7.66(s, 1H), 7.50 (s, 1H), 7.16-7.24 (m, 1H), 4.91 (br. s., 0.5H), 4.54 (d,J=12.5 Hz, 0.5H), 4.16-4.39 (m, 2.5H), 3.69-3.85 (m, 2.5H), 3.50-3.65(m, 0.5H), 3.38 (s, 3H), 3.20-3.32 (m, 1H), 2.98-3.14 (m, 1.5H),2.52-2.82 (m, 2H), 2.04-2.13 (m, 1H), 1.28-1.43 (m, 3H), 0.91-0.98 (m,2H), 0.81-0.89 (m, 2H).

LC-MS: m/z 445.5 (M+H)⁺

(R)-6-cyclopropyl-5-(isoquinolin-5-yl)-2-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)nicotinonitrile(Compound 386; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 9.30-9.40 (m, 1H), 8.49-8.58 (m, 1H), 8.06 (d,J=8.3 Hz, 1H), 7.67-7.75 (m, 1H), 7.62-7.67 (m, 2H), 7.36-7.45 (m, 1H),4.95 (br. s., 0.5H), 4.58-4.61 (m, 0.5H), 4.27-4.49 (m, 2H), 4.14 (br.s., 0.5H), 3.59-3.73 (m, 1H), 3.11-3.39 (m, 4.5H), 1.45-1.55 (m, 2.5H),1.37 (dd, J=6.4, 4.4 Hz, 1.5H), 1.07-1.19 (m, 2H), 0.77-0.87 (m, 2H).LC-MS: m/z 480.1 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 387; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 9.40 (br. s., 1H), 8.56 (d, J=4.5 Hz, 1H), 8.10(d, J=8.0 Hz, 1H), 7.72-7.78 (m, 1H), 7.64-7.71 (m, 2H), 7.46 (dd,J=12.5, 5.8 Hz, 1H), 4.58 (dt, J=13.1, 2.1 Hz, 1H), 4.47 (d, J=12.0 Hz,1H), 4.09-4.26 (m, 0.5H), 3.80-3.86 (m, 1.5H), 3.08-3.44 (m, 5H),1.49-1.57 (m, 1H), 1.33 (br. s., 1H), 1.08-1.22 (m, 2H), 0.82-0.91 (m,2H), 0.41-0.72 (m, 4H).

LC-MS: m/z 506.7 (M+H)⁺

(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 390)

A mixture of 7-1 (410 mg, 1.01 mmol), 2-chloropyridin-4-ylboronic acid(237 mg, 0.95 mmol), K₂CO₃ (414 mg, 3.03 mmol) and Pd(PPh₃)₄ (40 mg,0.035 mmol) in DMF (2 mL) was stirred at 150° C. in the microwavereactor for 1 h. The resultant mixture was partitioned between EtOAc andwater, the organic phase was washed with water, brine and concentratedand purified by prepTLC (PE:EA=1:1) to give 375 mg of(R)-2′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4′-bipyridine-5-carbonitrile.¹H NMR (CHLOROFORM-d) δ 8.34-8.61 (m, 1H), 7.60 (s, 1H), 7.39 (d, J=1.0Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=11.8 Hz, 0.5H), 4.21-4.41 (m,2.5H), 3.68-3.91 (m, 2.5H), 3.54 (d, J=4.0 Hz, 1H), 3.25-3.45 (m, 4H),2.95-3.25 (m, 1H), 2.63-2.92 (m, 1H), 2.42-2.63 (m, 1H), 1.87-2.07 (m,1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.11-1.31 (m, 3.5H), 0.81-1.11 (m, 2H).LC-MS: m/z 440.1 (M+H)⁺

A mixture of(R)-2′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4′-bipyridine-5-carbonitrile(40 mg, 0.09 mmol), vinyl tributyl stananne (30 mg, 0.09 mmol), KOAc (10mg) and Pd(PPh₃)₄ (5 mg) in DMF (2 mL) was stirred at 120° C. in themicrowave reactor for 20 min. The resulting mixture was concentrated andpurified by prepTLC (PE: EA=1:1) to give 25 mg of the title product. ¹HNMR (CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.31-7.45 (m,1H), 7.22 (dd, J=5.0, 1.8 Hz, 1H), 6.87 (dd, J=17.6, 10.8 Hz, 1H), 6.27(dd, J=17.6, 1.0 Hz, 1H), 5.41-5.71 (m, 1H), 4.90 (m, 0.5H), 5.51 (m,6.5H), 4.16-4.44 (m, 3H), 3.74 (t, J=6.1 Hz, 3H), 3.38 (s, 4H), 3.31 (d,J=4.0 Hz, 1H), 3.14 (br. s., 2H), 2.59 (t, J=6.0 Hz, 2H), 1.86-2.06 (m,1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.24-1.33 (m, 1.5H), 1.10-1.24 (m, 2H),0.83-1.10 (m, 2H). LC-MS: m/z 432.6 (M+H)⁺

(R)-2′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4′-bipyridine-5-carbonitrile(Compound 401)

¹H NMR (CHLOROFORM-d) δ 8.34-8.61 (m, 1H), 7.60 (s, 1H), 7.39 (d, J=1.0Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=11.8 Hz, 0.5H), 4.21-4.41 (m,2.5H), 3.68-3.91 (m, 2.5H), 3.54 (d, J=4.0 Hz, 1H), 3.25-3.45 (m, 4H),2.95-3.25 (m, 1H), 2.63-2.92 (m, 1H), 2.42-2.63 (m, 1H), 1.87-2.07 (m,1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.11-1.31 (m, 3.5H), 0.81-1.11 (m, 2H).LC-MS: m/z 440.1 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 391; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.41 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.11 (d,J=8.0 Hz, 1H), 7.68-7.81 (m, 2H), 7.61-7.67 (m, 1H), 7.45-7.56 (m, 1H),4.58 (d, J=11.5 Hz, 1H), 4.46 (d, J=13.1 Hz, 1H), 3.49-4.23 (m, 2.5H),3.16-3.33 (m, 2.5H), 1.58-1.69 (m, 1H), 1.42-1.54 (m, 1H), 1.17 (t,J=4.9 Hz, 2H), 1.00-1.10 (m, 3H), 0.76-0.87 (m, 4H), 0.69 (br. s., 1H),0.41-0.62 (m, 3H); LC-MS: m/z 464.2 (M+H)

(R)-1-(4-(6-cyclopropyl-5-(4-fluorophenyl)-3-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methylpiperazin-1-yl)-3-methoxypropan-1-one(Compound 392)

Step 1

(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (2g, 6.3 mmol) was dissolved in MeOH (5 mL) and NaOH (20% wt aq, 10 mL)and the reaction solution was heated to reflux overnight. The resultantsolution was concentrated and then dissolved in MeOH (10 mL), treatedwith SOCl₂ (0.1 ml) and then heated to reflux for 2 h. The resultingsolution was concentrated, washed with brine and exacted with EA (50mL). The organic phase was dried, concentrated and purified with flashcolumn (EA:PE=1:3) to give (R)-methyl5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinate as a whitesolid (804 mg, 50% yield).

Step 2

Following the same procedure as General procedure 1, step F, method 1.

Step 3

Following the same procedure as General procedure 1, step H.

Step 4

(R)-methyl6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinate(500 mg, 1.1 mmol) and 2 mL hydrazine hydrate was dissolved in 10 mLethanol. The reaction mixture was heated reflux overnight and cooleddown to rt. The mixture was filtered and the residue was washed withcold ethanol. 200 mg title compound was obtained without furtherpurification.

Step 5

(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotine-hydrazide(200 mg, 0.44 mmol) was dissolved in trimethoxymethane (25 mL). Thereaction mixture was heated to reflux overnight. The rest oftrimethoxymethane was removed under reduced pressure and purified byprep-TLC to give 50 mg of title compound. ¹H NMR (CHLOROFORM-d) δ 9.33(s, 1H), 8.51 (d, J=6.0 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J=7.8 Hz, 1H),7.62-7.89 (m, 2H), 7.27 (s, 1H), 4.63-4.78 (m, 2H), 4.47-4.63 (m, 1H),3.55-3.84 (m, 3H), 3.39 (s, 4H), 3.19 (dd, J=13.3, 3.5 Hz, 1H),2.91-3.12 (m, 2H), 2.66-2.88 (m, 3H), 2.44-2.66 (m, 2H), 1.28-1.43 (m,1.5H), 1.15-1.28 (m, 3.5H), 1.12 (br. s., 1H), 0.80-1.06 (m, 2H); LC-MS:m/z 466.2 (M+H).

2-(4-(cyclopropanecarbonyl)-3-(trifluoromethyl)piperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 397; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (t, J=6.4 Hz, 1H), 8.07 (d,J=8.0 Hz, 1H), 7.60-7.76 (m, 3H), 7.35-7.49 (m, 1H), 5.39 (br. s.,0.5H), 4.28-4.86 (m, 3.5H), 3.70-3.97 (m, 1H), 3.44 (d, J=14.3 Hz, 1H),3.23-3.39 (m, 1H), 1.68-1.91 (m, 1H), 1.53 (td, J=7.8, 3.5 Hz, 1H),1.08-1.23 (m, 3H), 0.77-1.07 (m, 5H). LC-MS: m/z 492.2 (M+H)⁺

6-cyclopropyl-5-(isoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-(trifluoromethyl)piperazin-1-yl)nicotinonitrile(Compound 398; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.35 (br. s., 1H), 8.55 (t, J=6.0 Hz, 1H), 8.07(d, J=8.0 Hz, 1H), 7.60-7.80 (m, 3H), 7.42 (dd, J=19.3, 5.5 Hz, 1H),5.29-5.48 (m, 0.5H), 4.71-4.92 (m, 1.5H), 4.44-4.62 (m, 1H), 4.02 (d,J=13.3 Hz, 0.5H), 3.63-3.86 (m, 2.5H), 3.33-3.51 (m, 3.5H), 3.19-3.32(m, 2H), 2.75-2.94 (m, 1H), 2.52-2.75 (m, 1H), 2.06 (br. s., 1H), 1.52(tq, J=8.0, 4.1 Hz, 1H), 1.10-1.22 (m, 2H), 0.76-0.93 (m, 2H). LC-MS:m/z 510.4 (M+H)⁺

6-cyclopropyl-5-(isoquinolin-5-yl)-2-(3-(trifluoromethyl)-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)nicotinonitrile(Compound 399; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (t, J=6.5 Hz, 1H), 8.07 (d,J=8.0 Hz, 1H), 7.55-7.80 (m, 3H), 7.32-7.45 (m, 1H), 5.26-5.49 (m,0.5H), 4.45-5.03 (m, 2.5H), 3.72-3.95 (m, 2H), 3.22-3.52 (m, 5H), 1.54(tq, J=8.0, 4.2 Hz, 1H), 1.10-1.22 (m, 2H), 0.78-0.94 (m, 3H). LC-MS:m/z 534.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 402; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.55 (d, J=5.8 Hz, 1H), 8.08(d, J=8.0 Hz, 1H), 7.52-7.77 (m, 3H), 7.44 (t, J=6.0 Hz, 1H), 4.93 (br.s., 0.5H), 4.25-4.48 (m, 2.5H), 4.21 (br. s., 0.5H), 3.95 (br. s., 2H),3.66-3.86 (m, 1.5H), 3.56-3.66 (m, 1H), 3.28-3.47 (m, 1H), 2.99-3.28 (m,2H), 2.49-2.77 (m, 1H), 1.40-1.57 (m, 3H), 1.11-1.40 (m, 2H), 0.75-1.04(m, 2H); LC-MS: m/z 442.2 (M+H).

(R)-6-cyclopropyl-5-(3-(dimethylamino)phenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 413; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.61-7.69 (m, 1H), 7.29-7.34 (m, 1H), 6.65-6.83(m, 3H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.14-4.34 (m,2.5H), 3.70-3.87 (m, 2.5H), 3.56 (t, J=11.2 Hz, 0.5H), 3.34-3.46 (m,3H), 3.00-3.28 (m, 8.5H), 2.54-2.83 (m, 2H), 2.14-2.23 (m, 1H),1.29-1.43 (m, 3H), 1.07-1.20 (m, 2H), 0.84-1.01 (m, 2H). LC-MS: m/z448.4 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(methylamino)phenyl)nicotinonitrile(Compound 414; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.63 (s, 1H), 7.23-7.27 (m, 1H), 6.72 (d, J=7.8Hz, 1H), 6.62-6.68 (m, 1H), 6.56-6.62 (m, 1H), 4.91 (br. s., 0.5H), 4.54(d, J=13.6 Hz, 0.5H), 4.15-4.33 (m, 2.5H), 3.70-3.88 (m, 2.5H),3.52-3.62 (m, 0.5H), 3.39 (s, 3H), 3.00-3.28 (m, 2.5H), 2.89 (s, 3H),2.65-2.83 (m, 1H), 2.51-2.65 (m, 1H), 2.14-2.21 (m, 1H), 1.30-1.47 (m,3H), 1.10-1.19 (m, 2H), 0.89-0.98 (m, 2H). LC-MS: m/z 434.5 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 409; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.54 (d, J=4.5 Hz, 1H), 8.07(d, J=8.0 Hz, 1H), 7.60-7.84 (m, 3H), 7.44 (dd, J=12.3, 6.0 Hz, 1H),4.71-4.73 (m, 0.5H), 4.56 (d, J=11.8 Hz, 1H), 4.38-4.50 (m, 1H),4.07-4.19 (m, 0.5H), 3.91 (d, J=11.0 Hz, 0.5H), 3.69-3.83 (m, 3H), 3.51(s, 3H), 3.20-3.29 (m, 1.5H), 3.13 (br. s., 1H), 2.61-2.70 (m, 2H), 1.52(ddd, J=12.0, 7.9, 4.6 Hz, 1H), 1.40 (br. s., 1H), 1.12-1.20 (m, 2H),0.80-0.90 (m, 2H), 0.48-0.77 (m, 4H). LC-MS: m/z 482.6 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 419; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.40 (br. s., 1H), 8.48-8.69 (m, 1H), 8.11 (d,J=8.0 Hz, 1H), 7.63-7.86 (m, 3H), 7.44-7.55 (m, 1H), 4.70-4.73 (m,0.5H), 4.57 (dd, J=13.1, 2.0 Hz, 1H), 4.41-4.52 (m, 1H), 4.13 (d, J=7.8Hz, 0.5H), 3.94 (br. s., 2H), 3.69-3.82 (m, 1H), 3.13-3.26 (m, 3H),2.50-2.71 (m, 2H), 1.48-1.57 (m, 1H), 1.39-1.48 (m, 1H), 1.12-1.21 (m,2H), 0.86-0.91 (m, 2H), 0.42-0.69 (m, 4H). LC-MS: m/z 468.5 (M+H)⁺

(R)-5-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)isoquinoline2-oxide (Compound 420)

¹H NMR (CHLOROFORM-d) δ 8.88 (br. s., 1H), 8.15 (d, J=6.5 Hz, 1H), 7.81(d, J=8.3 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.63 (s, 1H), 7.52-7.58 (m,1H), 7.44-7.52 (m, 1H), 4.94 (br. s., 0.5H), 4.55-4.59 (m, 0.5H),4.21-4.44 (m, 2.5H), 3.57-3.86 (m, 3H), 3.34-3.40 (m, 4H), 3.19-3.22 (m,1.5H), 2.58-2.86 (m, 2H), 1.47-1.55 (m, 1H), 1.30-1.38 (m, 3H),1.09-1.21 (m, 2H), 0.78-0.95 (m, 2H). LC-MS: m/z 472.4 (M+H)⁺

6-cyclopropyl-5-(isoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile(Compound 421; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.35 (br. s., 1H), 8.53 (d, J=5.0 Hz, 1H), 8.06(d, J=8.3 Hz, 1H), 7.68-7.75 (m, 1H), 7.60-7.67 (m, 2H), 7.42 (d, J=5.8Hz, 1H), 3.39-3.85 (m, 10H), 3.38 (s, 3H), 2.63-2.75 (m, 2H), 1.46-1.55(m, 1H), 1.08-1.18 (m, 2H), 0.75-0.85 (m, 2H). LC-MS: m/z 442.5 (M+H)⁺

2-(4-(cyclopropanecarbonyl)-3-(difluoromethyl)piperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 422; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.37 (br. s., 1H), 8.56 (br. s., 1H), 8.09 (d,J=8.0 Hz, 1H), 7.60-7.79 (m, 3H), 7.43 (d, J=10.3 Hz, 1H), 6.09 (br. s.,1H), 4.97-5.45 (m, 4H), 3.12-3.89 (m, 3H), 1.98-2.08 (m, 1H), 1.80-1.87(m, 1H), 1.00-1.21 (m, 4H), 0.83-0.92 (m, 4H). LC-MS: m/z 474.5 (M+H)⁺

2-(4-(cyclopropanecarbonyl)-3-(2,2,2-trifluoroethyl)piperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 423; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.55 (dd, J=5.8, 3.5 Hz, 1H), 8.08(d, J=8.0 Hz, 1H), 7.59-7.81 (m, 3H), 7.33-7.50 (m, 1H), 5.24 (br. s.,0.5H), 4.34 (d, J=13.1 Hz, 1H), 4.26-4.50 (m, 2.5H), 3.69 (br. s.,0.5H), 3.20-3.45 (m, 2H), 3.13 (br. s., 0.51H), 2.58-2.75 (m, 2H), 1.77(br. s., 1H), 1.47-1.61 (m, 1H), 1.09-1.24 (m, 4H), 0.77-0.93 (m, 4H).LC-MS: m/z 506.5 (M+H)⁺

(R)-2-cyclopropyl-2′-ethyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4-bipyridine-5-carbonitrile(Compound 426)

Compound 390 (18 mg) in EtOH was treated with Pd/C and hydrogenated atroom temperature and normal pressure to give the title compound as awhite solid. 1H NMR (CHLOROFORM-d) δ 8.63 (d, J=4.8 Hz, 1H), 7.63 (s,1H), 7.23 (d, J=4.5 Hz, 2H), 4.92 (br. s., 1H), 4.55 (d, J=12.8 Hz, 1H),4.14-4.43 (m, 3H), 3.64-3.89 (m, 3H), 3.57 (br. s., 1H), 3.40 (s, 3H),3.32 (d, J=11.8 Hz, 1H), 3.14 (d, J=14.3 Hz, 1H), 2.94 (q, J=7.4 Hz,2H), 2.65-2.83 (m, 1H), 2.39-2.65 (m, 1H), 2.03 (td, J=8.0, 3.9 Hz, 2H),1.25-1.42 (m, 8H), 1.11-1.25 (m, 3H), 1.01 (dd, J=7.8, 3.0 Hz, 2H).LC-MS: m/z 434.2 (M+H)⁺

Compound 430 (General Procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.41 (dd, J=7.9, 1.4 Hz, 1H), 8.14 (s, 1H),7.72-7.84 (m, 1H), 7.57-7.71 (m, 2H), 4.93 (d, J=13.3 Hz, 0.5H), 4.55(d, J=13.3 Hz, 0.5H), 4.14-4.43 (m, 3H), 3.69-3.90 (m, 3H), 3.53-3.68(m, 1H), 3.34-3.46 (m, 3H), 3.27 (t, J=11.2 Hz, 1H), 2.97-3.22 (m, 2H),2.54-2.84 (m, 2H), 1.55-1.80 (m, 2H), 1.43 (d, J=6.5 Hz, 2H), 1.18-1.38(m, 3H), 1.09 (br. s., 1H), 0.70-0.99 (m, 2H).

LC-MS: m/z 473.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-methylisoquinolin-5-yl)nicotinonitrile(Compound 433)

¹H NMR (CHLOROFORM-d) δ 9.23 (s, 1H), 7.93-8.03 (m, 1H), 7.50-7.66 (m,3H), 7.21 (d, J=6.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz,0.5H), 4.19-4.42 (m, 2.5H), 3.83 (d, J=12.3 Hz, 0.5H), 3.65-3.78 (m,2H), 3.56 (d, J=16.8 Hz, 0.5H), 3.37 (s, 3H), 3.31 (d, J=13.1 Hz, 1H),2.98-3.25 (m, 1.5H), 2.68-2.84 (m, 1H), 2.53-2.68 (m, 5H), 1.47-1.57 (m,1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.29-1.36 (m, 1.5H), 1.13 (dd, J=6.5, 4.0Hz, 2H), 0.76-0.84 (m, 2H). LC-MS: m/z 470.2 (M+H)⁺

(R)-6-cyclopropyl-5-(1-methoxyisoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 434)

¹H NMR (CHLOROFORM-d) δ 8.32 (dd, J=7.5, 1.3 Hz, 1H), 7.98 (d, J=6.0 Hz,1H), 7.52-7.65 (m, 3H), 6.94 (t, J=5.9 Hz, 1H), 4.85 (br. s., 0.5H),4.55 (d, J=12.8 Hz, 0.5H), 4.20-4.40 (m, 2.5H), 4.15 (s, 3H), 3.66-3.89(m, 3H), 3.38 (s, 3H), 3.31 (d, J=8.3 Hz, 1H), 3.17 (d, J=13.3 Hz,1.5H), 2.65-2.84 (m, 1H), 2.51-2.65 (m, 1H), 1.48-1.60 (m, 1H), 1.42 (m,1.5H), 1.29-1.36 (m, 1.5H), 1.03-1.19 (m, 2H), 0.81 (dd, J=8.0, 3.0 Hz,2H). LC-MS: m/z 486.2 (M+H)⁺

(1R,2R)-ethyl2-((R)-4-(3-cyano-6-cyclopropyl-5-(isoquinolin-5-yl)pyridin-2-yl)-2-methylpiperazine-1-carbonyl)cyclopropanecarboxylate (Compound 435)

¹H NMR (CHLOROFORM-d) δ 9.34 (s, 1H), 8.53 (d, J=5.8 Hz, 1H), 8.06 (d,J=8.0 Hz, 1H), 7.62-7.80 (m, 3H), 7.42 (t, J=5.9 Hz, 1H), 4.87 (br. s.,0.5H), 4.38-4.65 (m, 1.5H), 4.33 (d, J=12.0 Hz, 2H), 4.19 (q, J=7.0 Hz,2H), 3.62-3.85 (m, 0.5H), 3.46 (d, J=13.1 Hz, 0.5H), 3.10-3.40 (m, 2H),2.36 (br. s., 1H), 2.17-2.31 (m, 1H), 2.09 (br. s., 1H), 1.38-1.45 (m,2H), 1.22-1.37 (m, 6H), 1.03-1.22 (m, 2H), 0.69-0.94 (m, 2H). LC-MS: m/z461.2 (M+H)⁺

(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)isoquinoline2-oxide (Compound 439)

¹H NMR (CHLOROFORM-d) δ 8.87 (br. s., 1H), 8.06-8.26 (m, 1H), 7.70-7.83(m, 2H), 7.61-7.69 (m, 1H), 7.54 (br. s., 2H), 4.59 (d, J=7.0 Hz, 1H),4.47 (d, J=12.5 Hz, 1H), 3.51-4.30 (m, 3H), 3.32 (br. s., 1H), 3.17 (br.s., 1H), 1.96-2.10 (m, 1H), 1.75 (br. s., 1H), 1.43-1.54 (m, 1H),1.14-1.23 (m, 2H), 1.00-1.12 (m, 2H), 0.81-0.94 (m, 4H), 0.38-0.73 (m,4H). LC-MS: m/z 480.2 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)-N-(vinylsulfonyl)ethenesulfonamide(Compound 440; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.60-7.64 (m, 1H), 7.50-7.56 (m, 2H), 7.29-7.37(m, 3H), 7.01-7.16 (m, 2H), 6.26-6.40 (m, 2H), 6.11-6.25 (m, 2H), 4.92(s, 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.19-4.37 (m, 2.5H), 3.73-3.79 (m,3H), 3.52-3.61 (m, 0.5H), 3.39 (s, 3H), 3.28 (t, J=10.4 Hz, 1H),3.02-3.14 (m, 1H), 2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 1.98-2.07 (m,1H), 1.27 (s, 3H), 1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H). LC-MS: m/z600.2 (M+H)⁺

(R,E)-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)-4-(dimethylamino)but-2-enamide(Compound 441; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.68 (s, 1H), 7.53-7.60 (m, 1H),7.41-7.53 (m, 1H), 7.31 (s, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.86 (s, 1H),6.61 (d, J=15.3 Hz, 1H), 4.83 (s, 0.5H), 4.46 (d, J=11.0 Hz, 0.5H), 4.22(d, J=9.8 Hz, 2.5H), 3.90 (s, 1.5H), 3.67-3.81 (m, 2.5H), 3.52 (s,0.5H), 3.28-3.41 (m, 3H), 3.24 (s, 1H), 3.04-3.15 (m, 1H), 2.94-3.04 (m,1H), 2.88 (s, 2H), 2.82 (s, 6H), 2.57 (d, J=15.8 Hz, 1H), 1.97-2.08 (m,1H), 1.33-1.40 (m, 2H), 1.18-1.30 (m, 2H), 1.02-1.15 (m, 2H), 0.89 (s,2H). LC-MS: m/z 531.3 (M+H)⁺

(R)-6-cyclopropyl-5-(2-hydroxyquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 442)

1H NMR (CHLOROFORM-d) δ 7.88 (d, J=9.5 Hz, 1H), 7.63-7.70 (m, 1H),7.43-7.63 (m, 3H), 6.80 (d, J=9.5 Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (d,J=13.1 Hz, 0.5H), 4.15-4.45 (m, 3H), 3.66-3.87 (m, 2H), 3.40 (s, 2H),3.29 (t, J=9.7 Hz, 1H), 3.11-3.22 (m, 1H), 2.66-2.88 (m, 1H), 2.48-2.66(m, 1H), 1.96-2.10 (m, 1H), 1.36-1.56 (m, 1.5H), 1.08-1.36 (m, 3.5H),0.97 (dd, J=7.8, 3.0 Hz, 2H). LC-MS: m/z 472.3 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 443; General procedure 5, Step W):

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.3 Hz, 1H), 7.59-7.67 (m, 1H),7.35-7.45 (m, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.89 (dd, J=17.3, 10.8 Hz,1H), 6.29 (d, J=17.3 Hz, 1H), 5.58 (d, J=10.8 Hz, 1H), 4.87 (br. s.,1H), 4.56 (br. s., 1H), 4.30 (d, J=13.3 Hz, 1H), 4.13 (br. s., 1H),3.58-3.88 (m, 1H), 3.33 (d, J=10.0 Hz, 1H), 3.20 (br. s., 2H), 1.91-2.09(m, 1H), 1.38-1.51 (m, 1.5H), 1.11-1.38 (m, 2.5H), 0.87-1.08 (m, 6H),0.79-0.87 (m, 2H). LC-MS: m/z 414.4 (M+H)⁺

(R)-2-cyclopropyl-6-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 444; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 7.59-7.69 (m, 1H), 7.34-7.43 (m, 1H), 7.15-7.27(m, 1H), 6.89 (dd, J=17.6, 10.8 Hz, 1H), 6.23-6.37 (m, 1H), 5.58 (d,J=11.5 Hz, 1H), 4.94 (br. s., 1H), 4.20-4.48 (m, 2H), 3.51-3.79 (m, 1H),3.37 (d, J=5.5 Hz, 1H), 3.05-3.34 (m, 4H), 1.87-2.07 (m, 1H), 1.42-1.51(m, 2H), 1.13-1.42 (m, 3H), 0.95-1.08 (m, 2H). LC-MS: m/z 456.8 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 485; General procedure 5, Step W)

¹H NMR (CHLOROFORM-d) δ 8.77 (br. s., 1H), 7.96 (br. s., 1H), 7.80-7.92(m, 2H), 7.12-7.27 (m, 1H), 6.82 (d, J=17.6 Hz, 1H), 6.06 (d, J=10.8 Hz,1H), 4.67 (d, J=12.3 Hz, 1H), 4.54 (d, J=11.5 Hz, 2H), 4.24 (br. s.,1H), 3.67 (br. s., 1H), 3.33 (br. s., 1H), 3.18 (br. s., 1H), 1.93 (br.s., 1H), 1.67 (br. s., 1H), 1.25 (br. s., 2H), 1.04-1.23 (m, 3H),0.89-1.04 (m, 3H), 0.47 (d, J=4.8 Hz, 2H), 0.39 (br. s., 2H). LC-MS: m/z440.2 (M+H)⁺

Compound 527 (General Procedure 5, Step W)

¹H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.7 Hz, 1H), 7.65 (s, 1H), 7.38 (s,1H), 7.23 (d, J=4.1 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.28 (d,J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.55 (d, J=13.2 Hz, 1H), 4.43(d, J=12.6 Hz, 1H), 4.03-4.16 (m, 1H), 3.91 (br. s., 2H), 3.65-3.82 (m,1H), 3.40-3.53 (m, 1H), 3.02-3.32 (m, 3H), 2.49-2.69 (m, 2H), 1.98-2.10(m, 1H), 1.13-1.38 (m, 3H), 1.01 (dd, J=7.5, 3.4 Hz, 2H), 0.63 (br. s.,1H), 0.55 (br. s., 1H), 0.32-0.51 (m, 2H). LC-MS: m/z 444.3 (M+H)⁺

(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 498; General procedure 5, Step W)

¹H NMR (CHLOROFORM-d) δ 8.54-8.72 (m, 1H), 7.57-7.74 (m, 1H), 7.38 (d,J=1.0 Hz, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.88 (dd, J=17.3, 10.8 Hz,1H), 6.28 (dd, J=17.4, 1.1 Hz, 1H), 5.48-5.63 (m, 1H), 4.56 (dd, J=13.2,1.9 Hz, 1H), 4.45 (d, J=13.1 Hz, 1H), 4.11 (br. s., 1H), 3.65-3.88 (m,2H), 3.32 (q, J=9.6 Hz, 2H), 3.20 (d, J=12.0 Hz, 1H), 2.98-3.15 (m, 1H),2.04 (tt, J=8.0, 4.7 Hz, 1H), 1.30-1.39 (m, 1H), 1.14-1.25 (m, 2H),0.96-1.07 (m, 2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H), 0.41-0.54 (m,2H). LC-MS: m/z 482.5 (M+H)⁺

(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 500; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.60-7.71 (m, 1H), 7.41(s, 1H), 7.26 (dd, J=5.0, 1.3 Hz, 1H), 6.90 (dd, J=17.4, 10.9 Hz, 1H),6.31 (d, J=17.1 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H), 4.72-4.99 (m, 0.5H),4.54 (d, J=13.1 Hz, 0.5H), 4.22-4.49 (m, 2H), 3.74 (d, J=13.6 Hz, 1H),3.56 (br. s., 1H), 3.40 (br. s., 1H), 3.32 (td, J=8.6, 3.9 Hz, 1H),2.95-3.25 (m, 2H), 2.68 (br. s., 1H), 2.44-2.65 (m, 2H), 2.00-2.19 (m,1H), 1.16-1.45 (m, 3H), 0.95-1.12 (m, 3H), 0.90 (t, J=6.8 Hz, 1H).LC-MS: m/z 418.6 (M+H)⁺

(R)-2-cyclopropyl-6-(4-(4,4-dimethoxybutanoyl)-3-methylpiperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile(Compound 606; General procedure 5, Step W)

¹H NMR (CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.38 (s,1H), 7.23 (dd, J=5.0, 1.5 Hz, 1H), 6.81-6.93 (m, 1H), 6.28 (d, J=11.0Hz, 1H), 5.56 (d, J=11.0 Hz, 1H), 4.88 (s, 0.5H), 4.24-4.53 (m, 1.5H),4.24-4.36 (m, 2.5H), 3.78 (d, 0.5H), 3.54 (t, 0.5H), 3.27-3.37 (m, 4H),3.02-3.18 (m, 1.5H), 2.35-2.56 (m, 2H), 1.92-2.06 (m, 4H), 1.38 (d,1.5H), 1.28 (d, 1.5H), 1.18-1.21 (m, 2H), 0.99-1.02 (m, 2H). LC-MS: m/z476.2 (M+H)⁺

(R)-2-cyclopropyl-6-(3-methyl-4-(4-oxobutanoyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile(Compound 607), which was obtained as the by-product of Compound 606

¹H NMR (CHLOROFORM-d) δ 9.90 (s, 1H), 8.65 (d, J=5.0 Hz, 1H), 7.64 (s,1H), 7.38 (s, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.88 (q, 1H), 6.28 (d, 1H),5.56 (d, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=12.8 Hz, 0.5H), 4.25-4.37(m, 2.5H), 3.80 (br. s., 0.5H), 3.60 (br. s., 0.5H), 3.03-3.38 (m, 3H),2.62-2.89 (m, 4.5H), 2.03 (m, 1H), 1.42 (d, 1.5H), 1.28 (d, 1.5H),1.18-1.21 (m, 2H), 0.99-1.10 (m, 2H). LC-MS: m/z 430.2 (M+H)⁺

(S)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile(Compound 587; General procedure 5, Step W)

¹H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.62-7.73 (m, 1H), 7.39(s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H),6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.56 (d, J=13.1 Hz,1H), 4.43 (d, J=11.3 Hz, 1.5H), 4.09 (d, J=8.8 Hz, 0.5H), 3.93 (d, J=5.0Hz, 2H), 3.75-3.82 (m, 1.5H), 3.43 (br. s., 1H), 3.16-3.32 (m, 1.5H),3.02-3.16 (m, 1H), 2.43-2.71 (m, 2H), 2.00-2.09 (m, 1H), 1.67 (s, 1H),1.16-1.25 (m, 2H), 0.95-1.08 (m, 2H), 0.40-0.80 (m, 4H). LC-MS: m/z444.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(quinoxalin-6-yl)nicotinonitrile(Compound 445; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.90 (d, J=3.0 Hz, 2H), 8.05-8.34 (m, 2H), 7.85(d, J=8.5 Hz, 1H), 7.74 (s, 1H), 4.92 (br. s., 0.5H), 4.26-4.56 (m, 3H),3.57-3.84 (m, 3H), 3.31-3.38 (m, 4H), 3.13-3.16 (m, 1.5H), 2.27-2.78 (m,2H), 2.04-2.16 (m, 1H), 1.41 (d, J=5.8 Hz, 1.5H), 1.30 (d, J=6.0 Hz,1.5H), 1.22 (br. s., 2H), 0.94-1.06 (m, 2H). LC-MS: m/z 457.2 (M+H)⁺

Compound 446 (General Procedure 3, Step N, method 1)

1H NMR (CHLOROFORM-d) δ 7.58-7.67 (m, 1H), 7.38-7.50 (m, 2H), 7.32 (dd,J=7.7, 1.6 Hz, 2H), 6.49 (dd, J=16.6, 10.0 Hz, 1H), 6.25 (d, J=16.6 Hz,1H), 6.06 (d, J=10.0 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.1 Hz,0.5H), 4.13-4.41 (m, 3H), 3.71-3.87 (m, 2H), 3.49-3.63 (m, 1H), 3.39 (s,3H), 3.21-3.34 (m, 4H), 2.95-3.21 (m, 2H), 2.51-2.81 (m, 2H), 1.91-2.17(m, 1H), 1.73 (br. s., 2H), 1.23-1.50 (m, 5H), 0.94-1.23 (m, 4H). LC-MS:m/z 524.2 (M+H)⁺

(S)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)propanamide(Compound 447; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 8.57 (s, 1H), 7.70 (s, 1H), 7.57-7.64 (m, 1H),7.47-7.56 (m, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 4.90(br. s., 0.5H), 4.47-4.65 (m, 1.5H), 4.18-4.30 (m, 2.5H), 3.73-3.81 (m,2.5H), 3.48-3.64 (m, 0.5H), 3.37 (s, 3H), 3.21-3.31 (m, 1H), 2.95-3.18(m, 1.5H), 2.53-2.79 (m, 2H), 2.04-2.12 (m, 1H), 1.83 (d, J=7.0 Hz, 3H),1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.11-1.18 (m, 2H),0.89-1.03 (m, 2H). LC-MS: m/z 510.1 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)ethanesulfonamide(Compound 448; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.38-7.49 (m, 2H), 7.30-7.34 (m,1H), 7.26 (dd, J=8.0, 1.3 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.90 (br. s.,0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.13-4.40 (m, 2.5H), 3.67-3.93 (m,2.5H), 3.51-3.66 (m, 0.5H), 3.38 (s, 3H), 3.02-3.32 (m, 4.5H), 2.55-2.84(m, 2H), 2.00-2.11 (m, 1H), 1.38-1.44 (m, 4H), 1.24-1.31 (m, 2H),1.12-1.21 (m, 2H), 0.90-1.03 (m, 2H). LC-MS: m/z 512.1 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)methacrylamide(Compound 449; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.83 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H),7.51-7.57 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 5.83(s, 1H), 5.43-5.54 (m, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.3 Hz,0.5H), 4.13-4.36 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.55 (t, J=11.3 Hz,0.5H), 3.35-3.46 (m, 3H), 3.20-3.31 (m, 1H), 2.96-3.17 (m, 1.5H), 2.81(s, 2H), 2.51-2.77 (m, 2H), 2.03-2.19 (m, 4H), 1.38 (d, J=6.3 Hz, 1.5H),1.28 (d, J=6.5 Hz, 1.5H), 1.10-1.18 (m, 2H), 0.88-1.02 (m, 2H). LC-MS:m/z 488.1 (M+H)⁺

(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)phenyl)propiolamide(Compound 451; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.35-7.47 (m, 1H), 7.28 (s, 1H),7.23-7.27 (m, 1H), 7.15-7.22 (m, 2H), 6.63 (dd, J=16.6, 9.8 Hz, 1H),6.26-6.39 (m, 1H), 6.01 (d, J=9.8 Hz, 1H), 4.52 (d, J=12.5 Hz, 1H), 4.40(d, J=12.3 Hz, 1H), 4.07-4.24 (m, 1H), 3.65-3.90 (m, 1H), 3.22-3.52 (m,1.5H), 3.10 (s, 1.5H), 2.03-2.10 (m, 1H), 1.29-1.36 (m, 1H), 1.14-1.21(m, 2H), 0.93-1.12 (m, 4H), 0.85-0.92 (m, 1H), 0.76-0.85 (m, 2H),0.60-0.71 (m, 1H), 0.38-0.60 (m, 3H). LC-MS: m/z 518.2 (M+H)⁺

(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)phenyl)-N-(vinylsulfonyl)ethenesulfonamide(Compound 452; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.63 (s, 1H), 7.49-7.58 (m, 2H), 7.33-7.36 (m,1H), 7.31 (dt, J=6.7, 2.3 Hz, 1H), 7.07 (d, J=9.8 Hz, 1H), 7.10-7.13 (m,1H), 6.28-6.38 (m, 2H), 6.14-6.22 (m, 2H), 4.41-4.62 (m, 2.5H),3.98-4.18 (m, 1H), 3.75-3.90 (m, 1H), 3.09-3.33 (2.5, 1H), 2.00-2.07 (m,1H), 1.15-1.25 (m, 3H), 0.97-1.11 (m, 4H), 0.86-0.92 (m, 1H), 0.82 (dd,J=7.8, 2.3 Hz, 2H), 0.39-0.67 (m, 4H). LC-MS: m/z 608.2 (M+H)⁺

(R)—N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)phenyl)-2-fluoro-N-methylacrylamide(Compound 453; General procedure 3, Step N, method 2)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.43-7.54 (m, 1H), 7.34 (d, J=7.8Hz, 1H), 7.17-7.26 (m, 2H), 5.44 (d, J=3.3 Hz, 1H), 5.18-5.38 (m, 1H),4.82-5.11 (m, 2H), 4.54 (d, J=12.3 Hz, 1H), 4.10-4.40 (m, 3H), 3.75 (br.s., 2H), 3.57 (d, J=7.8 Hz, 1H), 3.35-3.48 (m, 6H), 3.28 (br. s., 1H),3.14 (d, J=10.5 Hz, 1H), 2.94-3.10 (m, 1H), 2.73 (br. s., 1H), 2.60 (br.s., 1H), 2.19 (s, 1H), 1.90-2.10 (m, 1H), 1.78 (br. s., 1H), 1.23-1.51(m, 8H), 1.06-1.23 (m, 2H), 0.78-1.06 (m, 3H). LC-MS: m/z 506.2 (M+H)⁺

(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)phenyl)acrylamide(Compound 454; General procedure 3, Step N, method 1)

¹H NMR (CHLOROFORM-d) δ 7.73-7.80 (m, 2H), 7.63 (s, 1H), 7.51-7.59 (m,1H), 7.42 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.40-6.54 (m, 1H),6.31 (dd, J=16.8, 10.3 Hz, 1H), 5.81 (d, J=10.3 Hz, 1H), 4.51 (d, J=12.3Hz, 1H), 4.39 (d, J=12.3 Hz, 1H), 3.92-4.27 (m, 1H), 3.51-3.94 (m, 1H),3.25 (m, 1H), 2.85-3.42 (m, 3H), 2.08-2.15 (m, 1H), 1.29-1.36 (m, 1H),1.13-1.20 (m, 2H), 0.94-1.11 (m, 4H), 0.86-0.93 (m, 1H), 0.75-0.85 (m,2H), 6.68 (d, J=12.5 Hz, 1H), 0.40-0.54 (m, 3H). LC-MS: m/z 482.2 (M+H)⁺

Compound 455 (General Procedure 3, Step N, Method 2)

¹H NMR (CHLOROFORM-d) 7.61 (s, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.31-7.36(m, 1H), 5.87 (s, 1H), 4.83-5.04 (m, 1H), 4.19-4.42 (m, 3H), 3.76 (br.s., 2H), 3.56 (br. s., 1H), 3.36-3.49 (m, 6H), 3.30 (br. s., 1H),2.91-3.20 (m, 4H), 2.74 (br. s., 1H), 2.68 (br. s., 1H), 2.61 (br. s.,1H), 1.93-2.02 (m, 1H), 1.15-1.45 (m, 16H), 0.99 (dd, J=7.8, 2.8 Hz,2H), 0.76-0.94 (m, 2H). LC-MS: m/z 512.2 (M+H)⁺

Compound 456 (General Procedure 3, Step N, Method 2)

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.40 (d,J=7.8 Hz, 1H), 7.29-7.37 (m, 2H), 4.10-4.39 (m, 3H), 3.70-3.90 (m, 2H),3.66 (s, 1H), 3.49 (s, 1H), 3.38 (s, 5H), 3.30 (d, J=14.8 Hz, 1H), 3.14(br. s., 2H), 2.71-2.91 (m, 2H), 2.48-2.71 (m, 2H), 2.05 (dt, J=7.8, 4.0Hz, 2H), 1.13-1.42 (m, 8H), 0.91-1.08 (m, 2H). LC-MS: m/z 486.2 (M+H)⁺

(R)-6-cyclopropyl-5-(1-hydroxyisoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 457; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 10.93 (s, 1H), 8.51 (dd, J=6.8, 2.3 Hz, 1H),7.51-7.67 (m, 3H), 6.32 (s, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8Hz, 0.5H), 4.18-4.41 (m, 2.5H), 3.53-3.92 (m, 3.5H), 3.40 (s, 1H),3.16-3.38 (m, 2.5H), 2.51-2.83 (m, 2H), 1.61 (br. s., 1H), 1.39-1.49 (m,1.5H), 1.31-1.39 (m, 1.5H), 1.14 (dd, J=8.3, 4.8 Hz, 2H), 0.79-0.93 (m,2H). LC-MS: m/z 472.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(3-methylisoquinolin-5-yl)nicotinonitrile(Compound 458; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 9.25 (s, 1H), 8.00 (dd, J=7.2, 1.6 Hz, 1H),7.54-7.67 (m, 3H), 7.16-7.27 (m, 1H), 4.57 (d, J=12.5 Hz, 1H), 4.46 (d,J=12.5 Hz, 1H), 3.62-4.63 (m, 2H), 3.10-3.40 (m, 2.5H), 2.67 (d, J=4.5Hz, 3H), 2.25-2.49 (m, 0.5H), 1.74 (br. s., 1H), 1.54 (dtd, J=12.7, 3.9,1.9 Hz, 2H), 1.13-1.23 (m, 2H), 0.95-1.13 (m, 2H), 0.77-0.91 (m, 4H),0.70 (br. s., 1H), 0.39-0.60 (m, 3H). LC-MS: m/z 478.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)nicotinonitrile(Compound 459)

A mixture of(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(300 mg), pentane-2,4-dione (100 mg) and TFA (1 drop) in cyclohexane wasrefluxed for 3 h. After evaporation, the residue was dissolved in CH₃CNand some Na₂SO4 was added followed by select-F-TEDA-BF₄ (800 mg). Themixture was refluxed for overnight. After evaporation, the residue waspurified by pre-TLC to give the title compound (75 mg). ¹H NMR(CHLOROFORM-d) δ 7.86 (s, 1H), 7.58-7.75 (m, 2H), 7.47 (t, J=8.0 Hz,1H), 7.10-7.26 (m, 2H), 6.33 (dt, J=6.0, 1.8 Hz, 1H), 4.91 (br. s.,0.5H), 4.42-4.63 (m, 2.5H), 4.13-4.40 (m, 2.5H), 3.65-3.95 (m, 2.5H),3.39 (s, 3H), 3.21-3.32 (m, 1H), 2.99-3.20 (m, 2H), 2.52-2.81 (m, 2H),2.00-2.29 (m, 1H), 1.35-1.53 (m, 1.5H), 1.23-1.35 (m, 1.5H), 1.07-1.23(m, 2H), 0.92-1.07 (m, 2H). LC-MS: m/z 486.2 (M+H)⁺

(R)-6-Cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-methyl-1-oxoisoindolin-4-yl)nicotinonitrile(Compound 460; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 7.93-7.88 (m, 1H), 7.61-7.55 (m, 2H), 7.45 (dd,J=7.5, 0.9 Hz, 1H), 4.97 (ddd, J=13.1, 10.1, 1.5 Hz, 1H), 4.42-4.15 (m,5H), 3.90-3.49 (m, 3H), 3.39 (d, J=5.2 Hz, 3H), 3.32 (dd, J=13.1, 3.6Hz, 1H), 3.26-3.09 (m, 4H), 2.85-2.53 (m, 2H), 2.12-1.88 (m, 1H), 1.17(dd, J=7.5, 3.1 Hz, 3H), 0.96 (dd, J=7.9, 3.2 Hz, 2H), 0.90 (t, J=6.8Hz, 3H).

LC-MS: m/z 474.6 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(2-methyl-1-oxoisoindolin-4-yl)nicotinonitrile(Compound 461; General procedure 1, Step I)

¹H NMR (400 MHz, CDCl₃) δ=7.93 (d, J=7.5 Hz, 1H), 7.64-7.57 (m, 2H),7.53-7.47 (m, 1H), 7.44 (s, 1H), 4.93-4.21 (m, 6H), 4.21-2.84 (m, 6H),1.82-1.65 (m, 2H), 1.55-1.29 (m, 4H), 1.17 (dd, J=7.0, 3.8 Hz, 2H),1.10-0.97 (m, 2H), 0.95 (dd, J=7.8, 3.2 Hz, 2H), 0.84-0.75 (m, 2H).

LC-MS: m/z 458.6.3 (M+H)⁺

(R)-2-(4-(Cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-oxoisoindolin-4-yl)nicotinonitrile(Compound 464; General procedure 1, Step I)

¹H NMR (400 MHz, CDCl₃) δ 7.95 (dd, J=7.6, 0.8 Hz, 1H), 7.64-7.59 (m,2H), 7.51 (dd, J=5.4, 2.1 Hz, 1H), 6.76 (s, 1H), 5.07-4.24 (m, 6H), 3.22(d, J=59.5 Hz, 2H), 2.05 (dt, J=15.3, 7.7 Hz, 1H), 1.31 (s, 2H), 1.19(dd, J=4.4, 3.2 Hz, 2H), 0.96 (dd, J=7.9, 3.2 Hz, 2H), 0.90 (t, J=6.8Hz, 3H), 0.82 (dd, J=7.9, 2.4 Hz, 2H), 0.49 (ddd, J=18.9, 9.9, 4.8 Hz,3H). LC-MS: m/z 468.6 (M+H)⁺

(R)-2-(4-(Cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(2-methyl-1-oxoisoindolin-4-yl)nicotinonitrile(Compound 465; General procedure 1, Step I)

¹H NMR (400 MHz, CDCl₃) δ=7.90 (d, J=7.6 Hz, 1H), 7.61-7.54 (m, 2H),7.45 (d, J=7.5 Hz, 1H), 5.04-3.99 (m, 6H), 3.78-3.06 (m, 6H), 2.13-1.83(m, 1H), 1.31 (d, J=5.5 Hz, 4H), 1.20-1.14 (m, 2H), 1.09-0.99 (m, 2H),0.95 (dd, J=7.9, 3.2 Hz, 2H), 0.83 (dd, J=7.9, 1.3 Hz, 2H). LC-MS: m/z466.6 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2,3-dioxoindolin-7-yl)nicotinonitrile(Compound 513; General procedure 1, Step I)

A mixture of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(103.9 mg, 0.25 mol), 7-bromoisatin (67.8 mg, 0.30 mmol), Pd(PPh₃)₄ (29mg, 0.03 mmol), and K₂CO₃ (86.3 mg, 0.63 mmol) suspended in 5 mL of1,4-dioxane was subjected to microwave reaction at 120° C. for 1 h.After the reaction, the reaction mixture was concentrated in vacuo,residue was purified by column chromatography to afford the titlecompound. Yield: 14.1 mg (11.7%). ¹H NMR (400 MHz, CDCl₃) δ 7.75-7.65(m, 2H), 7.64 (s, 1H), 7.53 (dd, J=7.8, 1.2 Hz, 1H), 7.25 (d, J=7.7 Hz,1H), 4.62 (d, J=13.4 Hz, 1H), 4.49 (d, J=12.2 Hz, 1H), 4.24 (m, 1H),3.77 (m, 1H), 3.26 (m, 2H), 1.88-1.77 (m, 1H), 1.73 (s, 2H), 1.30-1.16(m, 3H), 1.16-0.96 (m, 4H), 0.83 (dd, J=7.9, 2.5 Hz, 2H), 0.52 (dd,J=17.5, 12.8 Hz, 3H). LC-MS: m/z 482.3 (M+H)⁺

(R)-5-(benzo[d]oxazol-6-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 466; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ: 8.18 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.68 (s,1H), 7.65 (d, J=1.0 Hz, 1H), 7.43 (dd, J=8.2, 1.6 Hz, 1H), 4.55 (d,J=12.5 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.18-4.34 (m, 1H), 3.91-4.18(m, 1H), 3.73 (br. s., 1H), 3.28 (br. s., 1H), 3.12 (br. s., 1H),2.00-2.12 (m, 1H), 1.73 (br. s., 1H), 1.44 (br. s., 1H), 1.18-1.24 (m,2H), 0.94-1.12 (m, 4H), 0.77-0.87 (m, 2H), 0.68 (br. s., 1H), 0.40-0.61(m, 3H). LC-MS: m/z 454.5 (M+H)⁺

(R)-5-(benzo[d]oxazol-6-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 467; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ: 8.15-8.21 (m, 1H), 7.84-7.90 (m, 1H), 7.67 (s,1H), 7.61-7.66 (m, 1H), 7.39-7.47 (m, 1H), 4.59 (br. s., 1H), 4.21-4.46(m, 3H), 3.43-3.61 (m, 1H), 3.39 (br. s., 1H), 3.18 (br. s., 1H),2.00-2.10 (m, 1H), 1.78 (br. s., 1H), 1.25-1.32 (m, 3H), 1.16-1.24 (m,2H), 1.00-1.11 (m, 2H), 0.93-1.00 (m, 2H), 0.83 (dd, J=7.8, 1.8 Hz, 2H).LC-MS: m/z 428.5 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(3-methylisoquinolin-5-yl)nicotinonitrile(Compound 471; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 9.26 (s, 1H), 7.96-8.06 (m, 1H), 7.55-7.69 (m,3H), 7.21 (d, J=15.1 Hz, 1H), 4.57 (dt, J=13.1, 2.3 Hz, 1H), 4.46 (d,J=12.3 Hz, 1H), 4.15 (br. s., 0.5H), 3.69-3.95 (m, 1.5H), 3.21-3.45 (m,3H), 3.04-3.21 (m, 2H), 2.67 (d, J=4.5 Hz, 3H), 1.40-1.61 (m, 2H),1.24-1.31 (m, 1H), 1.07-1.21 (m, 2H), 0.77-0.91 (m, 2H), 0.70 (br. s.,1H), 0.43-0.56 (m, 2H). LC-MS: m/z 520.2 (M+H)⁺

(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)phenyl)ethenesulfonamide(Compound 472; General procedure 3, Step N, method 2)

To a solution of(R)-5-(3-aminophenyl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(30 mg, 0.07 mmol) in DCM was added propiolic acid (5 mg, 0.07 mmol) andDCC (18 mg, 0.084 mmol). The mixture was stirred at 25° C. for 16 hours.TLC and LC-MS showed product and the mixture was purified by prep-TLC togive 15 mg of the compound. ¹H NMR (CHLOROFORM-d) δ 8.19 (s, 1H),7.66-7.77 (m, 1H), 7.62 (s, 1H), 7.47-7.56 (m, 1H), 7.36-7.47 (m, 1H),7.19 (d, J=7.8 Hz, 1H), 4.51 (d, J=12.0 Hz, 1.5H), 4.29-4.45 (m, 1.5H),4.08-4.29 (m, 1H), 3.42-3.87 (m, 1H), 3.13-3.42 (m, 1H), 2.99-3.13 (m,1H), 2.98 (s, 1H), 2.05-2.14 (m, 1H), 1.68-1.77 (m, 1H), 1.11-1.21 (m,3H), 1.04-1.11 (m, 1H), 0.93-1.04 (m, 3H), 0.76-0.86 (m, 2H), 0.66 (s,1H), 0.38-0.60 (m, 3H). LC-MS: m/z 480.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-hydroxyquinolin-5-yl)nicotinonitrile(Compound 476; General procedure, Step I)

¹H NMR (CHLOROFORM-d) δ 7.89 (d, J=9.5 Hz, 1H), 7.67 (s, 1H), 7.52-7.64(m, 3H), 6.81 (d, J=9.5 Hz, 1H), 4.53 (d, J=12.5 Hz, 2H), 4.41 (d,J=12.3 Hz, 2H), 3.28 (br. s., 2H), 3.11 (br. s., 1H), 1.96-2.07 (m, 2H),1.14-1.32 (m, 2H), 0.93-1.11 (m, 4H), 0.76-0.92 (m, 2H), 0.67 (br. s.,1H), 0.31-0.60 (m, 3H). LC-MS: m/z 490.2 (M+H)

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinylquinolin-5-yl)nicotinonitrile(Compound 475)

Step 1

To a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-hydroxyquinolin-5-yl)nicotinonitrile(50 mg, 0.104 mmol), Et3N (12 mg, 0.12 mmol) in DCM (2 mL) was addeddropwise Tf2O (30.3 mg, 0.107 mmol) at 0° C. and stirred at r.t. for 3h. Water was added and the organic layer was combined, dried,concentrated to give 50 mg product after prep-TLC.

Step 2

To a solution of(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinolin-2-yltrifluoromethanesulfonate (50 mg, 0.082 mmol), tributyl(vinyl)stannane(27 mg, 0.086 mmol), LiCl (5.2 mg, 0.123 mmol) in THF (2 mL) was addedPd(PPh₃)₄(4.7 mg, 0.0041 mmol) under N2 and the reaction mixture washeated to 85° C. for 2 h. The mixture was cooled and the solvent wasremoved. Product (9 mg) was obtained by prep-TLC. ¹H NMR (CHLOROFORM-d)δ 8.16 (t, J=9.3 Hz, 2H), 7.72-7.86 (m, 3H), 7.68 (d, J=8.5 Hz, 1H),7.04-7.14 (m, 2H), 6.34 (d, J=17.6 Hz, 1H), 5.73 (d, J=11.0 Hz, 1H),4.53 (d, J=12.5 Hz, 2H), 4.41 (d, J=12.3 Hz, 2H), 3.28 (br. s., 2H),3.11 (br. s., 1H), 1.67 (br. s., 2H), 0.95-1.16 (m, 6H), 0.77-0.95 (m,6H). LC-MS: m/z 490.2 (M+H).

2-(4-(cyclopropanecarbonyl)-6-fluoro-1,4-diazepan-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 477; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.48-8.65 (m, 1H), 8.08 (d, J=8.0Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.69 (m, 2H), 7.42 (d, J=6.0 Hz, 1H),4.99 (br. s., 0.5H), 4.84 (br. s., 0.5H), 4.72 (br. s., 1.5H), 4.60 (br.s., 1H), 4.49 (d, J=13.8 Hz, 1H), 4.17-4.39 (m, 2H), 3.76 (br. s.,0.5H), 3.32-3.57 (m, 2H), 3.22 (br. s., 1H), 1.70 (br. s., 1H), 1.54(br. s., 1H), 1.14-1.20 (m, 2H), 1.04-1.12 (m, 2H), 0.83-0.90 (m, 4H).LC-MS: m/z 456.1 (M+H)

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(Compound 479; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 7.70-7.81 (m, 2H), 7.65 (S, 1H), 4.49 (d, J=13.1Hz, 1H), 4.37 (d, J=12.3 Hz, 1H), 4.13 (d, J=14.8 Hz, 1H), 3.79 (s, 1H),3.25 (s, 1.5H), 3.08 (s, 1.5H), 2.19-2.28 (m, 1H), 1.64-1.80 (m, 1H),1.15-1.22 (m, 2H), 0.95-1.11 (m, 4H), 0.86-0.93 (m, 1H), 0.81 (dd,J=7.8, 2.3 Hz, 2H), 0.66 (s, 1H), 0.38-0.59 (m, 3H). LC-MS: m/z 442.2(M+H)⁺

6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2R)-2-(methoxymethyl)cyclopropanecarbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 480)

¹H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (dd, J=6.0, 1.5 Hz, 1H), 8.07(d, J=8.0 Hz, 1H), 7.65-7.74 (m, 3H), 7.43 (dd, J=6.0 Hz, 1H), 4.58 (br.s., 0.5H), 4.46 (d, J=11.8 Hz, 1H), 4.26 (br. s., 0.5H), 4.09 (br. s.,0.5H), 3.83 (br. s., 0.5H), 3.68 (br. s., 0.5H), 3.52 (dd, J=10.3, 5.3Hz, 1H), 3.29-3.41 (m, 4H), 3.23 (br. s., 2H), 1.67-1.75 (m, 2H),1.39-1.59 (m, 2H), 1.26-1.36 (m, 3H), 1.16-1.19 (m, 2H), 0.82-0.85 (m,3H), 0.55 (br. s., 2H), 0.48 (br. s., 2H). LC-MS: m/z 508.1 (M+H)⁺

Compound 481

¹H NMR (CHLOROFORM-d) δ 9.38 (br. s., 1H), 8.55 (d, J=5.3 Hz, 1H), 8.08(d, J=8.0 Hz, 1H), 7.66-7.75 (m, 3H), 7.44-7.47 (m, 1H), 4.45-4.59 (m,2.5H), 4.09-4.19 (m, 1H), 3.86 (s, 0.5H), 3.57-3.68 (m, 3.5H), 3.05-3.45(m, 2.5H), 1.93 (br. s., 1H), 1.51-1.54 (m, 1H), 1.18-1.25 (m, 6H),0.83-0.91 (m, 4H), 0.49-0.68 (m, 4H). LC-MS: m/z 508.3 (M+H)⁺

(R)-5-(benzo[d]oxazol-7-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 482; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 7.85 (dd, J=7.8, 1.0 Hz, 1H), 7.49(t, J=7.7 Hz, 1H), 7.42 (dd, J=7.5, 1.0 Hz, 1H), 4.58 (br. s., 1H), 4.32(d, J=13.1 Hz, 2H), 3.49-3.62 (m, 1H), 3.46 (br. s., 1H), 3.21 (br. s.,2H), 1.85-1.93 (m, 1H), 1.78 (br. s., 1H), 1.31-1.45 (m, 3H), 1.18-1.25(m, 2H), 1.00-1.11 (m, 2H), 0.89-0.99 (m, 2H), 0.84 (d, J=6.8 Hz, 2H).LC-MS: m/z 428.5 (M+H)⁺

(R)-5-(benzo[d]oxazol-7-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 483; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 7.82-7.87 (m, 1H), 7.79 (s, 1H),7.49 (t, J=7.8 Hz, 1H), 7.42 (dd, J=7.5, 1.0 Hz, 1H), 4.59 (d, J=12.8Hz, 1H), 4.47 (d, J=12.0 Hz, 1H), 3.95-4.20 (m, 2H), 3.79 (br. s., 1H),3.30 (br. s., 1H), 3.15 (br. s., 1H), 1.85-1.97 (m, 1H), 1.61 (br. s.,2H), 1.19-1.25 (m, 2H), 1.06 (d, J=16.8 Hz, 2H), 0.91-0.98 (m, 2H), 0.82(d, J=6.5 Hz, 2H), 0.68 (br. s., 1H), 0.40-0.61 (m, 3H). LC-MS: m/z454.5(M+H)⁺2-(4-(cyclopropanecarbonyl)-6-fluoro-3-methyl-1,4-diazepan-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 484; General procedure 4, Step R and S): ¹H NMR (CHLOROFORM-d)δ 9.40 (br. s., 1H), 8.56 (br. s., 1H), 8.12 (d, J=8.0 Hz, 1H),7.69-7.81 (m, 2H), 7.68 (d, J=1.0 Hz, 1H), 7.47-7.54 (m, 1H), 4.54-4.98(m, 6H), 3.25-3.44 (m, 1H), 3.17 (br. s., 1H), 1.77-1.89 (m, 1H),1.49-1.54 (m, 1H), 1.25-1.30 (m, 3H), 1.19-1.23 (m, 2H), 1.10 (br. s.,2H), 0.84-0.91 (m, 4H). LC-MS: m/z 470.2 (M+H)

(R)-5-(1-(cyanomethyl)-1H-pyrazol-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 486)

To a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(60 mg, 0.149 mmol) in DMF was added K₂CO₃ (42 mg, 0.298 mmol) and2-bromoacetonitrile (27 mg, 0.224 mmol). The resulting mixture wasstirred for 16 hours. Then the mixture was partitioned between EtOAc andwater, the organic layer was washed with water, brine and dried overNa₂SO₄, concentrated to give the crude which was purified by prep-TLC togive 25 mg of the product. ¹H NMR (CHLOROFORM-d) δ 7.72 (s, 1H), 7.69(s, 1H), 7.61 (s, 1H), 5.17 (s, 2H), 4.32-4.52 (m, 2.5H), 3.65-3.89 (m,1H), 4.01-4.22 (m, 1H), 3.55-4.92 (m, 1H), 2.89-3.33 (m, 2.5H),2.10-2.23 (m, 1H), 1.72 (s, 1H), 1.31-1.47 (m, 1H), 1.14-1.22 (m, 2H),0.92-1.09 (m, 4H), 0.75-0.86 (m, 2H), 0.39-0.63 (m, 4H). LC-MS: m/z442.2 (M+H)⁺

2-((R)-4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-(3-hydroxycyclopentyl)-1H-pyrazol-4-yl)nicotinonitrile(Compound 493)

Step 1

To a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(100 mg, 0.248 mmol) in CH₂Cl₂ was added cyclopent-2-enone (51 mg, 0.621mmol) and ScCl₃ (338 mg, 2.24 mmol). The mixture was stirred for 16hours at room temperature. The mixture was partitioned between EtOAc andwater. The organic layer was washed with water, brine and dried overNa₂SO₄, concentrated to give the crude which was purified by prep-TLC togive 50 mg of the product. LC-MS: m/z 485.3 (M+H)⁺

Step 2

a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(40 mg, 0.0825 mmol) in MeOH was added NaBH₄, the mixture was stirredfor 2 hours at room temperature. The mixture was partitioned betweenEtOAc and water. The organic layer was washed with water, brine anddried over Na₂SO₄, concentrated to give the crude which was purified byprep-TLC to give 15 mg of the product. ¹H NMR (CHLOROFORM-d) δ 7.56-7.70(m, 3H), 4.85 (br. s., 1H), 4.25-4.70 (m, 4H), 4.00-4.25 (m, 1H),3.50-3.90 (m, 1H), 2.95-3.41 (m, 3H), 2.12-2.41 (m, 6H), 1.90-2.03 (m,1H), 1.37-1.54 (m, 1H), 1.23-1.37 (m, 1H), 1.17-1.28 (m, 2H), 0.94-1.09(m, 4H), 0.76-0.85 (m, 2H), 0.39-0.64 (m, 4H). LC-MS: m/z 487.3 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)nicotinonitrile(Compound 502)

To a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(30 mg, 0.074 mmol) in DCM was added TEA (15 mg, 0.149 mmol) andmethanesulfonyl chloride (9.4 mg, 0.082 mmol) and the mixture wasstirred at r.t. for 2 h. The mixture was partitioned between EtOAc andwater. The organic layer was washed with H₂O, brine and dried overNa₂SO₄, concentrated to give the crude which was purified by prep-TLC togive 15 mg of the product. ¹H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 7.97(s, 1H), 7.65 (s, 1H), 4.40-4.60 (m, 2.5H), 4.09-4.25 (m, 1H), 3.53-3.90(m, 1H), 3.45 (s, 3H), 3.05-3.41 (m, 2.5H), 2.06-2.19 (m, 1H), 1.12-1.26(m, 3H), 0.95-1.12 (m, 4H), 0.89 (t, J=6.8 Hz, 1H), 0.75-0.85 (m, 2H),0.36-0.64 (m, 4H). LC-MS: m/z 481.2 (M+H)⁺

(R)-2-(4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)-1H-pyrazol-1-yl)acetamide(Compound 501)

To a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(30 mg, 0.0745 mmol) in DMF was added K₂CO₃ (21 mg, 0.149 mmol) and2-bromoacetamide (12 mg, 0.082 mmol). The mixture was stirred for 16hours at room temperature, then the mixture was partitioned betweenEtOAc and water. The organic layer was partitioned between EtOAc andwater, the organic layer was washed with water, brine and dried overNa₂SO₄ concentrated to give 25 mg of the product. ¹H NMR (CHLOROFORM-d)δ 7.75 (s, 1H), 7.57-7.69 (m, 2H), 6.43 (br. s., 1H), 6.04 (br. s., 1H),4.88 (s, 2H), 4.30-4.60 (m, 2.5H), 3.84-4.23 (m, 1H), 3.50-3.80 (m, 1H),3.00-3.45 (m, 2.5H), 2.13-2.25 (m, 1H), 1.92 (s, 1H), 1.71 (s, 1H),1.12-1.21 (m, 2H), 0.94-1.10 (m, 4H), 0.72-0.84 (m, 2H), 0.35-0.63 (m,4H). LC-MS: m/z 460.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-((methylthio)methyl)-1H-pyrazol-4-yl)nicotinonitrile(Compound 510)

To a solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile(50 mg, 0.124 mmol) in DMF was added NaH (10 mg, 0.248 mmol) and(chloromethyl)(methyl)sulfane (24 mg, 0.248 mmol). The mixture wasstirred for 2 hours at room temperature. The mixture was partitionedbetween EtOAc and water, the organic layer was washed with water, brineand dried over Na₂SO₄, concentrated to give the crude which was purifiedby prep-TLC to give 15 mg of the product. ¹H NMR (CHLOROFORM-d) δ 7.73(s, 1H), 7.59-7.68 (m, 2H), 5.20 (s, 2H), 4.28-4.48 (m, 2.5H), 4.26-4.30(m, 1H), 3.50-3.80 (m, 1H), 2.99-3.40 (m, 2.5H), 2.22-2.28 (m, 1H), 2.21(s, 3H), 1.73 (s, 1H), 1.30-1.48 (m, 1H), 1.14-1.23 (m, 2H), 0.94-1.10(m, 4H), 0.75-0.85 (m, 2H), 0.39-0.64 (m, 4H). LC-MS: m/z 463.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)nicotinonitrile(Compound 490):

¹H NMR (CHLOROFORM-d) δ 7.66 (s, 1H), 7.58-7.64 (m, 2H), 4.47 (d, J=12.3Hz, 1H), 4.25-4.41 (m, 3H), 3.97-4.18 (m, 3H), 3.77 (s, 1H), 3.23 (s,2H), 3.07 (s, 1H), 2.16-2.30 (m, 1H), 1.23-1.35 (m, 2H), 1.12-1.21 (m,2H), 0.95-1.09 (m, 4H), 0.74-0.87 (m, 2H), 0.38-0.64 (m, 4H). LC-MS: m/z446.2M+H)⁺

(R)-5-(benzo[d]thiazol-6-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 487; General procedure 1, Step I)

1H NMR (CHLOROFORM-d) δ 9.07 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.00 (d,J=1.5 Hz, 1H), 7.68-7.73 (m, 1H), 7.58 (dd, J=8.4, 1.6 Hz, 1H), 4.55 (d,J=12.3 Hz, 1H), 4.43 (d, J=12.3 Hz, 1H), 3.50 (d, J=9.0 Hz, 2H), 3.29(br. s., 2H), 3.13 (br. s., 1H), 2.04-2.12 (m, 1H), 1.29-1.40 (m, 2H),1.18-1.25 (m, 2H), 0.94-1.12 (m, 4H), 0.77-0.86 (m, 2H), 0.68 (br. s.,1H), 0.40-0.61 (m, 3H); LC-MS: m/z 470.2 (M+H).

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(furan-3-carbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 488; General procedure 4, Step R and S)

1H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.55 (dd, J=5.8, 2.0 Hz, 1H), 8.08(d, J=8.0 Hz, 1H), 7.64-7.79 (m, 4H), 7.41-7.50 (m, 2H), 6.59 (s, 1H),4.61 (dd, J=13.1, 2.0 Hz, 1H), 4.43 (br. s., 2H), 3.98 (br. s., 1H),3.73 (br. s., 1H), 3.22-3.36 (m, 1H), 3.07-3.22 (m, 1H), 1.50-1.57 (m,2H), 1.12-1.21 (m, 2H), 0.81-0.89 (m, 2H), 0.65-0.78 (m, 1H), 0.53-0.62(m, 1H), 0.47 (br. s., 2H). LC-MS: m/z 490.6 (M+H)⁺

(R)-methyl4-(3-cyano-6-cyclopropyl-5-(isoquinolin-5-yl)pyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(Compound 489; General procedure 4, Step R and S)

1H NMR (CHLOROFORM-d) δ 9.37 (br. s., 1H), 8.55 (br. s., 1H), 8.08 (d,J=8.0 Hz, 1H), 7.70-7.77 (m, 1H), 7.60-7.70 (m, 2H), 7.46 (dd, J=12.0,5.8 Hz, 1H), 4.50-4.60 (m, 1H), 4.37-4.47 (m, 1H), 4.17 (d, J=12.5 Hz,1H), 3.76 (s, 3H), 3.45-3.59 (m, 2H), 3.29 (ddd, J=12.9, 6.4, 3.8 Hz,1H), 3.13 (tdd, J=12.5, 7.2, 3.5 Hz, 1H), 1.47-1.57 (m, 1H), 1.34-1.47(m, 1H), 1.18 (dd, J=7.3, 4.0 Hz, 2H), 0.85-0.93 (m, 2H), 0.60-0.72 (m,1H), 0.48-0.60 (m, 2H), 0.36-0.48 (m, 1H). LC-MS: m/z 454.5 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-[3,3′-bipyridine]-5,5′-dicarbonitrile(Compound 494; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.92 (br. s., 2H), 7.99-8.07 (m, 1H), 7.63 (s,1H), 4.63 (d, J=12.8 Hz, 1H), 4.50 (d, J=12.3 Hz, 1H), 3.33 (br. s.,1H), 3.17 (m, 2H), 1.80-1.90 (m, 2H), 1.73 (m., 1H), 1.19-1.31 (m, 4H),0.94-1.12 (m, 4H), 0.76-0.88 (m, 2H), 0.36-0.60 (m, 4H). LC-MS: m/z439.5 (M+H)⁺

(R)-5-(cinnolin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 495; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ: 9.28 (d, J=2.0 Hz, 1H), 8.66 (d, J=8.5 Hz, 1H),7.88-7.97 (m, 1H), 7.72-7.85 (m, 2H), 7.66-7.72 (m, 2H), 4.60-4.74 (m,1.5H), 4.43-4.60 (m, 1.5H), 3.60-3.89 (m, 1H), 3.35 (br. s., 1H), 3.22(br. s., 1H), 1.49-1.58 (m, 1H), 1.16-1.36 (m, 4H), 0.99-1.16 (m, 2H),0.78-0.99 (m, 4H), 0.63-0.78 (m, 1H), 0.42-0.63 (m, 3H). LC-MS: m/z465.6 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinylpyrimidin-4-yl)nicotinonitrile(Compound 496)

The procedure was similar to the synthesis of Compound 390. ¹H NMR(CHLOROFORM-d) δ 8.67-8.84 (m, 1H), 8.07 (s, 1H), 7.43 (d, J=5.0 Hz,1H), 6.87-7.03 (m, 1H), 6.74 (dd, J=17.4, 1.6 Hz, 1H), 5.76-5.88 (m,1H), 4.68 (d, J=13.1 Hz, 1H), 4.55 (d, J=13.3 Hz, 1H), 4.07 (br. s.,1H), 3.88 (s, 1H), 3.66 (br. s., 1H), 3.33 (br. s., 1H), 3.17 (br. s.,1H), 2.34-2.47 (m, 1H), 1.96-2.08 (m, 2H), 1.30-1.42 (m, 2H), 1.00-1.11(m, 3H), 0.85-0.93 (m, 1H), 0.82 (dd, J=8.0, 2.5 Hz, 2H), 0.65 (br. s.,1H), 0.39-0.59 (m, 3H). LC-MS: m/z 441.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-methylisoquinolin-5-yl)nicotinonitrile(Compound 497; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.40 (dd, J=6.0, 2.0 Hz, 1H), 8.24 (d, J=8.3 Hz,1H), 7.68-7.76 (m, 1H), 7.31 (d, J=6.5 Hz, 2H), 4.58 (d, J=10.5 Hz, 1H),4.46 (d, J=12.5 Hz, 1H), 4.23 (br. s., 1H), 3.82 (br. s., 1H), 3.67 (br.s., 1H), 3.32 (br. s., 1H), 3.17 (br. s., 1H), 2.93-3.12 (m, 3H), 1.74(br. s., 1H), 1.47-1.57 (m, 2H), 1.14-1.22 (m, 2H), 1.00-1.12 (m, 2H),0.83 (dd, J=6.7, 4.6 Hz, 4H), 0.70 (br. s., 1H), 0.41-0.63 (m, 3H).LC-MS: m/z 478.3 (M+H)⁺

(R)-6′-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2′-cyclopropyl-6-vinyl-2,3′-bipyridine-5′-carbonitrile(Compound 499; General procedure 1, Step H)

The procedure was similar to the synthesis of Compound 390. ¹H NMR(CHLOROFORM-d) δ 7.95 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.39-7.45 (m,1H), 7.32-7.37 (m, 1H), 6.82-6.96 (m, 1H), 6.31 (dd, J=17.6, 1.3 Hz,1H), 5.49-5.59 (m, 1H), 4.58 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.5 Hz,1H), 4.19 (br. s., 0.5H), 4.06 (br. s., 0.5H), 3.78 (br. s., 0.5H), 3.60(br. s., 0.5H), 3.28 (br. s., 2H), 3.11 (br. s., 1H), 2.29-2.39 (m, 1H),1.67-1.79 (m, 1H), 1.32-1.45 (m, 1H), 1.18-1.25 (m, 2H), 0.96-1.12 (m,4H), 0.74-0.87 (m, 2H), 0.65 (br. s., 1H), 0.35-0.58 (m, 3H). LC-MS: m/z440.6 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(imidazo[1,2-a]pyrazin-3-yl)nicotinonitrile(Compound 503; General procedure 1, Step I)

¹H NMR (400 MHz, CDCl₃) δ=9.20 (s, 1H), 7.89 (dd, J=25.5, 17.4 Hz, 3H),7.73 (s, 1H), 4.66 (d, J=12.8 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 3.49 (s,4H), 3.36-3.10 (m, 2H), 2.15-1.83 (m, 3H), 1.53 (m, 1H), 1.08-0.95 (m,4H), 0.84 (m, 3H), 0.61-0.40 (m, 3H). LC-MS: m/z 454.1 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2,3-dioxoindolin-5-yl)nicotinonitrile(Compound 504; General procedure 1, Step I)

¹H NMR (400 MHz, CDCl₃) δ=8.38 (s, 1H), 7.68 (d, J=1.8 Hz, 1H),7.64-7.57 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 5.48-5.23 (m, 1H), 4.98 (m,1H), 3.38-3.05 (m, 2H), 2.14-1.88 (m, 4H), 1.01 (dd, J=7.9, 3.4 Hz, 3H),0.90 (dd, J=9.0, 4.7 Hz, 5H), 0.86-0.77 (m, 3H), 0.57-0.40 (m, 3H).LC-MS: m/z 482.2 (M+H)⁺

5-(4-acryloylmorpholin-2-yl)-2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 600)

A mixture of2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(morpholin-2-yl)nicotinonitrile(13 mg, 0.03 mmol), acryloyl chloride (1 drop) and TEA (1 drop) in 10 mLof DCM was stirred at r.t. for 10 mins. After the mixture was quenchedand worked up, the filtrate was concentrated and the residue waspurified by column chromatography (50% PE/EA) to afford 11 mg of titlecompound. ¹H NMR (CHLOROFORM-d) δ 7.86 (s, 1H), 6.48-6.69 (m, 1H),6.31-6.48 (m, 1H), 5.80 (d, J=9.3 Hz, 1H), 4.91 (d, J=13.1 Hz, 1H), 4.71(d, J=8.8 Hz, 1H), 4.44-4.63 (m, 1.5H), 4.05-4.34 (m, 4H), 3.92 (d,J=12.5 Hz, 0.5H), 3.74 (d, J=9.8 Hz, 1.5H), 3.35-3.52 (m, 1.5H),3.04-3.29 (m, 3H), 2.62 (t, J=11.3 Hz, 0.5H), 2.10 (br. s., 1H), 1.75(br. s., 1H), 1.40 (br. s., 1.5H), 1.27 (br. s., 1.5H), 1.13 (br. s.,2H), 1.03 (br. s., 4H), 0.81 (d, J=7.0 Hz, 2H). LC-MS: m/z 450.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile(Compound 613)

Step 1

A mixture of 8-4 (50 mg, 0.11 mmol), 5-chloropyridazin-3-ol (21 mg, 0.16mmol), CsF (33 mg, 0.22 mmol) and Pd(dppf)Cl₂(5 mg) in dioxane and waterwas heated at 100° C. for 1 hr. The reaction mixture was concentratedand the residue was purified by pre-TLC to afford 35 mg of titlecompound. ¹H NMR (CHLOROFORM-d) δ 12.68 (br. s., 1H), 7.97 (s, 1H), 7.65(s, 1H), 7.02 (br. s., 1H), 4.51-4.64 (m, 2.5H), 4.21 (br. s., 1H),3.56-3.84 (m, 1H), 3.17-3.32 (m, 2.5H), 1.99 (br. s., 1H), 1.71 (br. s.,1H), 1.24 (br. s., 3H), 1.01-1.08 (m, 4H), 0.72-0.92 (m, 2H), 0.32-0.64(m, 4H). LC-MS: m/z 431.1 (M+H)⁺

Step 2

A solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-hydroxypyridazin-4-yl)nicotinonitrile,Tf₂O and TEA in DCM was stirred for 1 hr. The reaction mixture waswashed with water, dried and concentrated. The residue was purified bypre-TLC to afford 150 mg of title compound. ¹H NMR (CHLOROFORM-d, 400MHz) δ 9.42 (br. s., 1H), 7.72 (s, 1H), 7.52 (s, 1H), 4.58-4.75 (m,2.5H), 4.32 (br. s., 0.5H), 4.00 (br. s., 0.5H), 3.73 (br. s., 1H),3.25-3.39 (m, 2.5H), 1.89-1.94 (m, 1H), 1.72 (br. s., 1H), 1.31 (br. s.,3H), 1.00-1.18 (m, 4H), 0.84 (d, J=6.3 Hz, 2H), 0.45-0.66 (m, 4H).

Step 3

A mixture of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile(50 mg, 0.09 mmol), potassium vinyltrifluoroborate (24 mg, 0.18 mmol),TEA(27 mg, 0.27 mmol) and Pd(dppf)Cl₂(5 mg) in i-PrOH and water washeated at 100° C. for 1 hr. The reaction mixture was concentrated andthe residue was purified by pre-TLC to afford 11 mg of title compound.¹H NMR (CHLOROFORM-d)

9.20 (br. s., 1H), 7.68 (br. s., 1H), 7.61 (br. s., 1H), 7.04-7.22 (m,1H), 6.36 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.8 Hz, 1H), 4.53-4.58 (m,2.5H), 4.17 (br. s., 1H), 3.72 (br. s., 1H), 3.19-3.34 (m, 1H), 1.94(br. s., 1H), 1.80 (br. s., 1H), 1.26 (br. s., 3H), 1.07 (br. s., 4H),0.82 (br. s., 2H), 0.46-0.65 (m, 4H). LC-MS: m/z 441.2 (M+H)⁺

(R)-5-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)pyridazin-3-yltrifluoromethanesulfonate (Compound 614):

¹H NMR (CHLOROFORM-d) δ 9.41 (s, 1H), 7.71 (s, 1H), 7.50 (d, J=1.3 Hz,1H), 4.93 (br. s., 0.5H), 4.56 (d, J=7.8 Hz, 0.5H), 4.47 (d, J=7.3 Hz,1.5H), 4.25-4.40 (m, 1H), 3.86 (d, J=12.5 Hz, 0.5H), 3.76 (br. s., 2H),3.57 (br. s., 0.5H), 3.36-3.48 (m, 4H), 3.30 (br. s., 0.5H), 3.11-3.24(m, 1H), 2.71 (br. s., 1H), 2.61 (br. s., 1H), 1.89-1.93 (m, 1H), 1.37(d, J=5.5 Hz, 1.5H), 1.22-1.32 (m, 3.5H), 1.08-1.22 (m, 2H). LC-MS: m/z555.1 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-vinylpyridazin-4-yl)nicotinonitrile(Compound 615)

The procedure is similar to Compound 613. ¹H NMR (CHLOROFORM-d) δ 9.20(br. s., 1H), 7.67 (s, 1H), 7.58-7.65 (m, 1H), 7.13 (dd, J=17.8, 11.0Hz, 1H), 6.37 (d, J=17.8 Hz, 1H), 5.79 (d, J=11.0 Hz, 1H), 4.92 (br. s.,0.5H), 4.48-4.62 (m, 0.5H), 4.35-4.48 (m, 1.5H), 4.31 (d, J=14.1 Hz,1H), 3.83 (d, J=13.3 Hz, 0.5H), 3.67-3.80 (m, 2H), 3.51-3.63 (m, 0.5H),3.30-3.45 (m, 4H), 3.13-3.28 (m, 1.5H), 2.65-2.82 (m, 1H), 2.51-2.65 (m,1H), 1.92-1.96 (m, 1H), 1.38 (d, J=5.5 Hz, 1.5H), 1.24-1.27 (m, 3.5H),1.07 (d, J=4.8 Hz, 2H). LC-MS: m/z 433.1 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-hydroxypyridazin-4-yl)nicotinonitrile(Compound 616)

¹H NMR (CHLOROFORM-d) δ 12.68 (br. s., 1H), 7.97 (s, 1H), 7.65 (s, 1H),7.02 (br. s., 1H), 4.51-4.64 (m, 2.5H), 4.21 (br. s., 1H), 3.56-3.84 (m,1H), 3.17-3.32 (m, 2.5H), 1.99 (br. s., 1H), 1.71 (br. s., 1H), 1.24(br. s., 3H), 1.01-1.08 (m, 4H), 0.72-0.92 (m, 2H), 0.32-0.64 (m, 4H).LC-MS: m/z 431.1 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)nicotinonitrile(Compound 640)

¹H NMR (CHLOROFORM-d) δ 7.85 (br. s., 1H), 7.60 (br. s., 1H), 6.95 (br.s., 1H), 4.50-4.63 (m, 2.5H), 4.21 (br. s., 1H), 3.84 (br. s., 3H), 3.69(br. s., 1H), 3.17-3.30 (m, 2.5H), 1.99 (br. s., 1H), 1.76 (br. s., 1H),1.22 (br. s., 3H), 1.07 (br. s., 4H), 0.81 (br. s., 2H), 0.51 (br. s.,4H). LC-MS: m/z 445.2 (M+H)⁺

(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)pyridazine-3-carbonitrile(Compound 641)

¹H NMR (CHLOROFORM-d) δ 9.51 (d, J=2.3 Hz, 1H), 7.93 (d, J=2.3 Hz, 1H),7.70 (s, 1H), 4.59-4.72 (m, 2.5H), 4.09-4.26 (m, 1H), 3.75 (br. s., 1H),3.23-3.39 (m, 2.5H), 1.82-1.95 (m, 1H), 1.65 (br. s., 1H), 1.26-1.34 (m,3H), 0.96-1.20 (m, 4H), 0.76-0.91 (m, 2H), 0.38-0.75 (m, 4H). LC-MS: m/z440.2 (M+H)⁺

(R)-2-(4-acetyl-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 516; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.07 (d,J=8.0 Hz, 1H), 7.64-7.74 (m, 3H), 7.43 (t, J=5.9 Hz, 1H), 4.91 (br. s.,0.5H), 4.57-4.53 (d, 0.5H), 4.18-4.39 (m, 2.5H), 3.6-3.77 (m, 1H), 3.34(br. s., 1H), 3.05-3.25 (m, 1.5H), 1.91 (br. s., 3H), 1.33-1.54 (m, 4H),1.14-1.17 (m, 2H), 0.82-0.85 (m, 2H). LC-MS: m/z 412.2 (M+H)⁺

6-cyclopropyl-2((R)-4((1S,2R)-2-ethoxycyclopropanecarbonyl)-3-methylpiperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 517; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.06 (d,J=8.0 Hz, 1H), 7.59-7.76 (m, 3H), 7.44 (t, J=6.8 Hz, 1H), 4.87-5.02 (m,0.5H), 4.61-4.64 (m, 0.5H), 4.12-4.43 (m, 2.5), 3.05-3.70 (m, 5.5H), 2.0(s, 1H), 1.76-1.86 (m, 1H), 1.40-1.62 (m, 3H), 1.27-1.35 (m, 2H),1.16-1.21 (m, 4H), 0.92-0.99 (m, 1H), 0.81-0.84 (m, 2H). LC-MS: m/z482.2 (M+H)⁺

6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 518; General procedure 4, Step R and S)

1H NMR (CHLOROFORM-d) δ 9.37 (s, 1H), 8.54 (dd, J=6.0, 2.0 Hz, 1H), 8.08(d, J=8.0 Hz, 1H), 7.73 (t, 1H), 7.64-7.69 (m, 2H), 7.46 (q, 1H), 4.73(m, 0.5H), 4.43-4.62 (m, 2.5H), 4.13-4.26 (m, 2H), 3.68-3.87 (m, 1.5H),3.50-3.60 (m, 3.5H), 3.19-3.30 (s, 2H), 1.97-2.19 (m, 2H), 1.50-1.54 (m,1H), 1.16-1.23 (m, 6H), 0.82-0.91 (m, 5H), 0.64-0.68 (m, 2H), 0.43-0.51(m, 2H). LC-MS: m/z 508.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(4-oxobutanoyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 519; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.91 (s, 1H), 9.38 (s, 1H), 8.55 (br. s., 1H),8.09 (d, J=8.0 Hz, 1H), 7.74 (t, 1H), 7.66-7.70 (m, 2H), 7.47 (q, 1H),4.55-4.58 (d, 1H), 4.44-4.47 (d, 1H), 4.09 (br. s., 1H), 3.90 (br. s.,1H), 3.07-3.40 (m, 2.5H), 2.69-2.91 (m, 3.5H), 2.05 (m, 2H), 14.53 (m,1H), 0.83-0.92 (m, 6H), 0.44-0.71 (br. s., 4H). LC-MS: m/z 480.2 (M+H)⁺

6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2R)-2-ethoxycyclopropanecarbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 526; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.35 (br. s., 1H), 8.53 (br. s., 1H), 8.07 (d,J=8.0 Hz, 1H), 7.68-7.74 (t, 1H), 7.64-7.67 (m, 2H), 7.45 (dd, J=5.8 Hz,1H), 4.58 (d, J=12.8 Hz, 1H), 4.49 (d, J=11.3 Hz, 1H), 4.13-4.27 (m,1.5H), 3.80 (br. s., 0.5H), 3.52-3.59 (m, 3H), 3.22 (br. s., 2H), 1.82(d, J=7.5 Hz, 1H), 1.47-1.57 (m, 2H), 1.17-1.20 (m, 6H), 0.82-0.99 (m,5H), 0.45-0.65 (m, 4H). LC-MS: m/z 508.3 (M+H)⁺

6-cyclopropyl-2-((R)-4-((1R,2R)-2-(hydroxymethyl)cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 505; General procedure 4, Step R and S)

¹H NMR (CHLOROFORM-d) δ 9.39 (br. s., 1H), 8.56 (br. s., 1H), 8.08 (d,J=8.0 Hz, 1H), 7.71-7.76 (m, 1H), 7.66-7.70 (m, 1H), 7.64 (s, 1H), 7.47(br. s., 1H), 4.18-4.89 (m, 4H), 3.25-3.80 (m, 5H), 2.01-2.08 (m, 1H),1.46-1.57 (m, 2H), 1.24-1.39 (m, 4H), 1.10-1.20 (m, 2H), 0.79-0.91 (m,3H). LC-MS: m/z 468.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(quinoxalin-5-yl)nicotinonitrile(Compound 531; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.88 (d, J=1.8 Hz, 1H), 8.91 (d, J=1.5 Hz, 1H),8.21 (dd, J=8.4, 1.4 Hz, 1H), 7.88 (t, J=8.4, 7.2 Hz, 1H), 7.79 (dd,J=7.2, 1.4 Hz, 1H), 7.73 (s, 1H), 4.53 (d, 1H), 4.56 (d, 1H), 4.53-4.27(m, 2.5H), 3.05-3.45 (m, 2.5H), 1.74 (br. s., 1H), 1.56-1.65 (m, 1H),0.97-1.26 (m, 6H), 0.42-0.87 (m, 8H). LC-MS: m/z 465.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(quinoxalin-5-yl)nicotinonitrile(Compound 532; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.89-8.92 (m, 2H), 8.22 (dd, J=8.4, 1.4 Hz, 1H),7.89 (t, J=8.3, 7.3 Hz, 1H), 7.79-7.81 (dd, J=8.3, 7.3 Hz, 1H), 7.75 (s,1H), 4.53 (d, J=13.1 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 4.14 (br. s.,0.5H), 3.75-3.89 (m, 1.5H), 3.07-3.37 (m, 5H), 1.62 (m, 1H), 1.19 (br.s., 2H), 0.48-0.84 (m, 6H). LC-MS: m/z 507.3 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinoxalin-5-yl)nicotinonitrile(Compound 579; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (dd, J=8.5, 1.3 Hz, 1H), 7.84(dd, J=8.3, 7.3 Hz, 1H), 7.67-7.74 (m, 1H), 7.01-7.12 (m, 1H), 6.50 (d,J=11.3 Hz, 1H), 5.84 (d, J=11.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (br.s., 0.5H), 4.19-4.40 (m, 2.5H), 3.68-3.78 (m, 2.5H), 3.58 (br. s.,0.5H), 3.39 (s, 3H), 3.02-3.31 (m, 2.5H), 2.58-2.75 (m, 2H), 1.86 (br.s., 1H), 1.62 (m, 1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.33 (d, J=6.3 Hz,1.5H), 1.16 (br. s., 2H), 0.81 (br. s., 2H). LC-MS: m/z 485.2 (M+H)⁺

(R,E)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-(2-(2-vinylquinoxalin-5-yl)vinyl)quinoxalin-5-yl)nicotinonitrile(Compound 604)

It was obtained as the by-product of Compound 579. ¹H NMR (CHLOROFORM-d)δ 9.23 (s, 1H), 9.09 (s, 1H), 8.17-8.20 (m, 2H), 8.08 (d, J=8.5 Hz, 1H),7.70-7.87 (m, 5H), 7.04-7.11 (q, 1H), 6.53 (d, J=11.3 Hz, 1H), 5.85 (d,J=11.3 Hz, 1H), 4.94 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H),4.26-4.37 (m, 2.5H), 3.75-3.84 (m, 2.5H), 3.59 (t, 0.5H), 3.40 (s, 3H),3.06-3.32 (m, 2.5H), 2.59-2.81 (m, 2H), 1.61-1.73 (m, 1H), 1.45 (d,J=6.3 Hz, 1.5H), 1.32 (d, J=6.3 Hz, 1.5H), 1.25-1.29 (m, 2H), 0.83-0.86(m, 2H). LC-MS: m/z 637.3 (M+H)⁺

(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylquinoxalin-5-yl)nicotinonitrile(Compound 605; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.83 (t,J=7.8 Hz, 1H), 7.62-7.77 (m, 2H), 6.97-7.13 (q, 1H), 6.50 (d, J=11.0 Hz,1H), 5.84 (d, J=11.0 Hz, 1H), 4.58-4.73 (m, 1.5H), 4.39-4.48 (m, 1.5H),3.87 (d, J=13.3 Hz, 0.5H), 3.74 (m, 2H), 3.42-3.60 (m, 1H), 3.39 (d,J=3.3 Hz, 3H), 2.93-3.17 (m, 2.5H), 2.53-2.83 (m, 2H), 2.16-2.33 (m,1H), 1.62 (br. s., 1H), 1.07-1.10 (m, 4H), 0.82-0.93 (m, 6H). LC-MS: m/z511.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinoxalin-5-yl)nicotinonitrile(Compound 618; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (dd, J=8.5, 1.3 Hz, 1H), 7.84(dd, J=8.3, 7.3 Hz, 1H), 7.67-7.74 (m, 2H), 7.02-7.07 (m, 1H), 6.50 (d,J=11.3 Hz, 1H), 5.82 (d, J=11.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (br.s., 0.5H), 4.19-4.33 (m, 3H), 3.93 (s, 2.5H), 3.58 (br. s., 0.5H),3.01-3.48 (m, 4H), 2.48-2.75 (m, 3H), 1.63 (m, 1H), 1.43 (d, J=6.3 Hz,1.5H), 1.35 (d, J=6.3 Hz, 1.5H), 1.16 (br. s., 2H), 0.82 (br. s., 2H).LC-MS: m/z 469.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylquinoxalin-5-yl)nicotinonitrile(Compound 644; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (dd, J=8.5, 1.3 Hz, 1H),7.70-7.72 (m, 2H), 7.01-7.12 (q, 1H), 6.50 (d, J=11.3 Hz, 1H), 5.84 (d,J=11.3 Hz, 1H), 4.71 (br. s., 0.5H), 4.52 (d, 1H), 4.41 (d, 1H), 4.12(br. s., 0.5H), 3.89 (br. s., 0.5H), 3.74 (m, 2H), 3.39 (s, 3H),3.01-3.31 (m, 3H), 2.59-2.83 (m, 2H), 1.58-1.68 (m, 1H), 0.97-1.32 (m,4H), 0.46-0.89 (m, 7H). LC-MS: m/z 509.1 (M+H)⁺

(R)-2′-bromo-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-3,4′-bipyridine-5-carbonitrile(Compound 508; General procedure 1, Step H)

¹H NMR CHLOROFORM-d) δ 8.46 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.57-7.61(m, 1H), 7.34 (dd, J=5.0, 1.5 Hz, 1H), 4.61 (d, J=12.8 Hz, 1H), 4.49 (d,J=13.6 Hz, 1H), 4.18-4.38 (m, 1H), 3.76 (br. s., 2H), 3.31 (br. s., 1H),3.15 (br. s., 1H), 1.93-2.08 (m, 1H), 1.72 (br. s., 1H), 1.33 (br. s.,1H), 1.17-1.26 (m, 2H), 0.95-1.12 (m, 4H), 0.76-0.91 (m, 2H), 0.66 (br.s., 1H), 0.35-0.60 (m, 3H). LC-MS: m/z 493.4 (M+H)⁺

(R)-2′-chloro-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-3′-fluoro-3,4′-bipyridine-5-carbonitrile(Compound 509; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.29 (d, J=5.0 Hz, 1H), 7.59-7.75 (s, 1H),7.11-7.41 (d, J=5.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.50 (d, J=12.5Hz, 1H), 4.06 (br. s., 1H), 3.75 (br. s., 1H), 3.65 (br. s., 1H), 3.31(br. s., 1H), 3.16 (br. s., 1H), 1.70-1.81 (m, 1H), 1.30-1.42 (m, 1H),1.13-1.25 (m, 2H), 0.94-1.13 (m, 4H), 0.75-0.87 (m, 2H), 0.66 (br. s.,1H), 0.35-0.60 (m, 3H). LC-MS: m/z 466.9 (M+H)⁺

(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)isoquinoline-1-carbonitrile(Compound 511)

¹H NMR (CHLOROFORM-d) δ 8.66 (dd, J=5.8, 1.8 Hz, 1H), 8.45 (d, J=8.3 Hz,1H), 7.87-7.97 (m, 1H), 7.80 (ddd, J=7.2, 2.1, 1.0 Hz, 1H), 7.70 (ddd,J=11.1, 5.8, 0.9 Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 4.61 (d, J=12.0 Hz,1H), 4.49 (d, J=12.8 Hz, 1H), 3.42-4.43 (m, 2H), 3.10-3.40 (m, 3H), 1.75(br. s., 1H), 1.38-1.47 (m, 2H), 0.95-1.12 (m, 2H), 0.75-0.93 (m, 6H),0.70 (br. s., 1H), 0.38-0.61 (m, 3H). LC-MS: m/z 489.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(1-hydroxyisoquinolin-5-yl)nicotinonitrile(Compound 547; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 10.95 (s, 1H), 8.53 (dd, J=6.4, 3.1 Hz, 1H),7.57-7.72 (m, 3H), 7.17 (br. s., 1H), 6.31 (dd, J=12.9, 7.4 Hz, 1H),4.38-4.61 (m, 2H), 4.15 (br. s., 0.5H), 3.69-3.95 (m, 1.5H), 3.03-3.41(m, 5H), 1.53-1.77 (m, 3H), 1.16 (dd, J=8.3, 4.5 Hz, 2H), 0.81-0.98 (m,2H), 0.47-0.64 (m, 3H). LC-MS: m/z 522.2 (M+H)⁺

(R)-5-(3-chloroisoquinolin-5-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 555; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.17 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.66-7.73(m, 2H), 7.64 (d, J=1.0 Hz, 1H), 7.49 (d, J=14.8 Hz, 1H), 4.61 (d,J=12.0 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H), 3.42-4.43 (m, 2H), 3.10-3.40(m, 3H), 1.69 (br. s., 1H), 1.39-1.57 (m, 2H), 1.15-1.23 (m, 2H), 1.08(br. s., 2H), 0.79-0.93 (m, 4H), 0.70 (br. s., 1H), 0.38-0.63 (m, 3H).LC-MS: m/z 498.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-hydroxyisoquinolin-5-yl)nicotinonitrile(Compound 566; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 11.20 (br. s., 1H), 8.52 (dd, J=7.0, 2.3 Hz,1H), 7.51-7.76 (m, 3H), 7.12-7.24 (m, 1H), 6.33 (dd, J=12.7, 7.4 Hz,1H), 4.56 (d, J=12.5 Hz, 1H), 4.44 (d, J=12.3 Hz, 1H), 3.52-4.35 (m,2H), 3.05-3.45 (m, 3H), 1.63 (td, J=7.8, 4.0 Hz, 1H), 1.27-1.45 (m, 2H),0.96-1.23 (m, 4H), 0.77-0.96 (m, 4H), 0.70 (br. s., 1H), 0.36-0.62 (m,3H). LC-MS: m/z 480.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(3-vinylisoquinolin-5-yl)nicotinonitrile(Compound 565; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.29 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.55-7.77(m, 3H), 7.31 (d, J=12.5 Hz, 1H), 6.88 (ddd, J=17.3, 10.6, 6.8 Hz, 1H),6.38 (ddd, J=17.2, 5.6, 1.3 Hz, 1H), 5.44-5.59 (m, 1H), 4.59 (d, J=11.8Hz, 1H), 4.47 (d, J=12.5 Hz, 1H), 3.55-4.35 (m, 2H), 3.05-3.45 (m, 3H),1.68-1.80 (m, 1H), 1.42-1.61 (m, 2H), 1.22-1.34 (m, 2H), 1.00-1.14 (m,2H), 0.76-0.92 (m, 4H), 0.71 (br. s., 1H), 0.39-0.63 (m, 3H). LC-MS: m/z490.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-methylisoquinolin-5-yl)nicotinonitrile(Compound 588; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 9.23 (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.53-7.67(m, 3H), 7.21 (d, J=6.5 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.1Hz, 0.5H), 4.15-4.43 (m, 2.5H), 3.86-4.02 (m, 2H), 3.68-3.83 (m, 0.5H),3.51-3.68 (m, 0.5H), 3.26-3.42 (m, 1H), 2.97-3.24 (m, 1.5H), 2.49-2.78(m, 5H), 1.49-1.58 (m, 1H), 1.41-1.49 (m, 1.5H), 1.30-1.40 (m, 1.5H),1.06-1.20 (m, 2H), 0.72-0.91 (m, 2H). LC-MS: m/z 456.2 (M+H)⁺

(R)-5-(5-chloro-2-vinylpyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 533; General procedure 1, Step H)

1H NMR (CHLOROFORM-d) δ 8.69-8.87 (m, 1H), 7.70-7.91 (m, 1H), 6.91 (dd,J=17.3, 10.5 Hz, 1H), 6.59-6.78 (m, 1H), 5.71-5.98 (m, 1H), 4.66 (d,J=12.8 Hz, 1H), 4.53 (d, J=12.5 Hz, 1H), 3.09-4.42 (m, 5H), 1.76-1.85(m, 1H), 1.39-1.46 (m, 1H), 1.21-1.25 (m, 2H), 0.99-1.10 (m, 4H), 0.90(t, J=6.9 Hz, 1H), 0.78-0.85 (m, 2H), 0.66 (br. s., 1H), 0.41-0.60 (m,3H). LC-MS: m/z 475.2 (M+H)⁺

Compound 541

Step 1:(R)-5-(6-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

To a solution of 4,6-dichloropyrimidine (50 mg, 0.32 mmol) in a mixtureof dimethoxyethane (3 mL) and a 2M aqueous sodium carbonate solution(0.6 mL) were added 8-4 (100 mg, 0.22 mmol) andtetrakis(triphenylphosphine)palladium(0) (20 mg, 0.1 eq) under nitrogenatmosphere, and the mixture was heated for 2 hours at 100° C. Aftercooling to ambient temperature, the separated organic layer wasevaporated under reduced pressure. The residue was taken up into ethylacetate, washed in turn with a 10% aqueous potassium carbonate solutionand brine, and dried over sodium sulfate. After evaporation, the residuewas purified on silica gel eluding with 5%-20% ethyl acetate inpetroleum ether to give 4-chloro-6-phenylpyrimidine (75 mg), 69% yield.¹H NMR (CHLOROFORM-d) δ 8.67-8.84 (m, 1H), 8.07 (s, 1H), 7.43 (d, J=5.0Hz, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.07 (br. s.,1H), 3.88 (s, 1H), 3.68 (br. s., 1H), 3.33 (br. s., 1H), 3.17 (br. s.,1H), 2.34-2.47 (m, 1H), 1.96-2.08 (m, 2H), 1.30-1.42 (m, 2H), 1.00-1.11(m, 3H), 0.85-0.93 (m, 1H), 0.82 (dd, J=8.0, 2.5 Hz, 2H), 0.65 (br. s.,1H), 0.39-0.59 (m, 3H). LC-MS: m/z 449.2 (M+H)⁺

Step 2:(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyrimidin-4-yl)nicotinonitrile(Compound 541)

A mixture of above(R)-5-(6-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(60 mg, 0.06 mmol) (60 mg, 0.13 mmol), vinyl potassium-trifluoroborate(25 mg, 0.2 mmol), Pd(PPh3)4 (3 mg, 0.1 eq), and CsF (40 mg, 0.26 mmol)were suspended in 5 mL of dioxane and 1 mL of water, the resultingmixture was refluxed for 1 h. After the reaction was complete, thereaction mixture was concentrated in vacuo, and the residue was purifiedby column chromatography to afford 35 mg of title compound as yellowsolid. 75% yield. ¹H NMR (CHLOROFORM-d) δ 9.16-9.30 (m, 1H), 7.93-8.07(m, 1H), 7.49-7.56 (m, 1H), 6.82 (dd, J=17.3, 10.5 Hz, 1H), 6.57 (dd,J=17.3, 1.0 Hz, 1H), 5.72-5.83 (m, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.55(d, J=12.3 Hz, 1H), 4.39-3.11 (br. s., 5H), 2.34-2.43 (m, 1H), 1.70 (br.s., 1H), 1.31-1.40 (m, 2H), 0.99-1.11 (m, 4H), 0.89-0.94 (m, 1H), 0.82(dd, J=7.9, 2.4 Hz, 2H), 0.64 (br. s., 1H), 0.41-0.58 (m, 3H). LC-MS:m/z 441.2 (M+H)⁺

(S)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyrimidin-4-yl)nicotinonitrile(Compound 578)

¹H NMR (CHLOROFORM-d) δ9.24 (d, J=1.3 Hz, 1H), 7.94-8.05 (m, 1H),7.46-7.58 (m, 1H), 6.82 (dd, J=17.3, 10.8 Hz, 1H), 6.57 (dd, J=17.3, 1.0Hz, 1H), 5.73-5.84 (m, 1H), 4.68 (d, J=12.5 Hz, 1H), 4.55 (d, J=12.3 Hz,1H), 4.08 (br. s., 1H), 3.76 (s, 1H), 3.66 (t, J=6.7 Hz, 1H), 3.40-3.58(m, 1H), 3.33 (br. s., 1H), 3.17 (br. s., 1H), 2.34-2.45 (m, 1H),1.29-1.35 (m, 2H), 1.00-1.11 (m, 4H), 0.89-0.92 (m, 1H), 0.82 (dd,J=7.9, 2.4 Hz, 2H), 0.64 (br. s., 1H), 0.43-0.58 (m, 3H). LC-MS: m/z441.2 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-vinylpyrimidin-4-yl)nicotinonitrile(Compound 621)

¹H NMR (CHLOROFORM-d) δ 9.24 (d, J=1.3 Hz, 1H), 7.82-8.04 (m, 1H),7.47-7.61 (m, 1H), 6.68-6.93 (m, 1H), 6.42-6.62 (m, 1H), 5.64-5.88 (m,1H), 4.88 (br. s., 1H), 4.29-4.57 (m, 3H), 4.17 (br. s., 1H), 3.93 (br.s., 2H), 3.74 (d, J=13.3 Hz, 1H), 3.47-3.63 (m, 1H), 3.29-3.41 (m, 1H),3.05-3.25 (m, 2H), 2.51-2.72 (m, 2H), 2.33-2.42 (m, 1H), 1.32-1.44 (m,2H), 1.22-1.28 (m, 3H), 1.02-1.11 (m, 2H). LC-MS: m/z 419.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-vinylpyrimidin-4-yl)nicotinonitrile(Compound 638)

¹H NMR (CHLOROFORM-d) δ 9.24 (s, 1H), 7.95-8.11 (m, 1H), 7.50-7.56 (m,1H), 6.74-6.87 (m, 1H), 6.48-6.65 (m, 1H), 5.74-5.89 (m, 1H), 4.67 (d,J=12.8 Hz, 1H), 4.53 (d, J=11.0 Hz, 1H), 4.10 (br. s., 0.5H), 3.83-3.93(m, 0.5H), 3.61-3.81 (m, 3H), 3.39 (s, 3H), 3.21-3.35 (m, 2H), 3.08-3.21(m, 1H), 2.72 (br. s., 1H), 2.65 (br. s., 1H), 2.33-2.43 (m, 1H),1.21-1.36 (m, 3H), 1.03-1.13 (m, 2H), 0.60 (br. s., 2H), 0.45 (br. s.,2H). LC-MS: m/z 459.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-vinylpyrimidin-4-yl)nicotinonitrile(Compound 639)

1H NMR (CHLOROFORM-d) δ 9.09-9.32 (m, 1H), 7.99 (s, 1H), 7.51 (s, 1H),6.81 (dd, J=17.3, 10.5 Hz, 1H), 6.56 (d, J=17.3 Hz, 1H), 5.78 (d, J=11.3Hz, 1H), 4.67-4.76 (m, 1H), 4.50 (d, J=14.6 Hz, 1H), 3.88 (d, J=13.6 Hz,1H), 3.68-3.79 (m, 2H), 3.60 (d, J=10.5 Hz, 1H), 3.39-3.55 (m, 1H),3.02-3.24 (m, 2H), 2.85-3.02 (m, 1H), 2.52-2.82 (m, 2H), 2.33-2.43 (m,1H), 1.92-2.05 (m, 1H), 1.23-1.31 (m, 2H), 1.00-1.10 (m, 5H), 0.83-0.92(m, 3H). LC-MS: m/z 461.3 (M+H)⁺

(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-vinylpyrimidin-4-yl)nicotinonitrile(Compound 597)

1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 6.80(dd, J=17.3, 10.8 Hz, 1H), 6.44-6.69 (m, 1H), 5.64-5.92 (m, 1H), 4.89(br. s., 0.5H), 4.52 (d, J=9.5 Hz, 0.5H), 4.28-4.46 (m, 2H), 3.65-3.95(m, 3H), 3.44-3.65 (m, 1H), 3.27-3.44 (m, 4H), 3.00-3.27 (m, 2H),2.51-2.81 (m, 2H), 2.25-2.47 (m, 1H), 1.14-1.44 (m, 5H), 0.93-1.14 (m,2H). LC-MS: m/z 433.2 (M+H)⁺

(R)-6-cyclopropyl-5-(6-(1-fluorovinyl)pyrimidin-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(Compound 602)

To a solution of(R)-5-(6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(80 mg 0.21 mmol), CuI (10 mg, 10%), and Pd(PPh3)2Cl2 (15 mg) in 5 ml ofDMF was added (1-fluorovinyl)(methyl)diphenylsilane (7.6 mg, 0.41 mmol).The mixture was stirred at room temperature for 2 h under nitrogenatmosphere. After removal of the solvent under reduced pressure, theresidue was purified by prep-TLC (20% ethyl acetate in petroleum ether)to afford 20 mg of pure product, 30% yield. ¹H NMR (CHLOROFORM-d)

9.25 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 6.11 (d, J=3.0 Hz, 1H), 5.99(d, J=3.0 Hz, 1H), 5.27 (dd, J=15.8, 3.0 Hz, 1H), 4.91 (br. s., 1H),4.54 (d, J=10.3 Hz, 1H), 4.31-4.49 (m, 1H), 3.71-3.78 (m, 1H), 3.49-3.63(m, 1H), 3.31-3.44 (m, 4H), 3.16-3.28 (m, 1H), 3.13 (br. s., 1H),2.51-2.81 (m, 2H), 2.30-2.44 (m, 1H), 1.35 (d, J=6.5 Hz, 2H), 1.25 (dd,J=4.3, 2.8 Hz, 3H), 1.04-1.13 (m, 2H). LC-MS: m/z 451.2 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-2%(prop-1-en-2-yl)-3,4% bipyridine-5-carbonitrile (Compound 544)

Synthesized according to the procedure described for Compound 602 exceptusing trimethyl(prop-1-en-2-yl)silane instead of(1-fluorovinyl)(methyl)diphenylsilane. ¹H NMR (CHLOROFORM-d) δ8.67 (d,J=5.0 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.16-7.27 (m, 1H), 5.92 (s,1H), 5.38 (s, 1H), 4.57 (d, J=12.3 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H),4.07 (br. s., 1H), 3.78 (br. s., 1H), 3.56-3.74 (m, 1H), 3.50 (s, 1H),3.29 (br. s., 1H), 3.14 (br. s., 1H), 2.26 (s, 3H), 1.98-2.10 (m, 1H),1.72 (br. s., 1H), 1.17-1.27 (m, 2H), 0.97-1.09 (m, 4H), 0.86-0.95 (m,1H), 0.76-0.84 (m, 2H), 0.66 (br. s., 1H), 0.40-0.59 (m, 3H). LC-MS: m/z453.2 (M+H)⁺

(R)-5-(2-aminopyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 507)

To a solution NH₃/MeOH (10 mL, 7 M) was added(R)-5-(2-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(40 mg, 0.09 mmol), the mixture was stirred at 50 C overnight. Afterremoval of the solvent under reduced pressure, the residue was purifiedby prep-TLC (30% ethyl acetate in petroleum ether) to afford 21 mg ofpure product, 51% yield. ¹H NMR (CHLOROFORM-d) δ 8.36 (d, J=5.3 Hz, 1H),7.97 (s, 1H), 6.90 (d, J=5.0 Hz, 1H), 5.25 (br. s., 2H), 4.64 (d, J=12.5Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 3.69 (br. s., 1H), 3.32 (br. s., 1H),3.26 (br. s., 1H), 3.15 (br. s., 2H), 2.32-2.45 (m, 1H), 2.03-2.08 (m,1H), 1.02-1.10 (m, 4H), 0.77-0.89 (m, 4H), 0.63 (br. s., 2H), 0.43-0.58(m, 3H). LC-MS: m/z 430.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-(dimethylamino)pyrimidin-4-yl)nicotinonitrile(Compound 506)

Synthesized according to the procedure described for Compound 507 exceptusing dimethylamine instead of NH₃.EtOH. ¹H NMR (CHLOROFORM-d) δ 8.38(d, J=5.0 Hz, 1H), 7.90-8.06 (m, 1H), 6.72 (d, J=5.0 Hz, 1H), 4.61 (d,J=12.8 Hz, 1H), 4.49 (d, J=12.5 Hz, 1H), 4.09-4.26 (m, 1H), 3.30-3.58(m, 2H), 3.26 (s, 6H), 3.16-3.24 (m, 1H), 3.11 (d, J=18.3 Hz, 1H),2.48-2.56 (m, 1H), 1.19-1.24 (m, 3H), 0.98-1.08 (m, 4H), 0.86-0.92 (m,1H), 0.76-0.84 (m, 2H), 0.64 (br. s., 1H), 0.40-0.58 (m, 3H). LC-MS: m/z458.3 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(2-(dimethylamino)pyrimidin-4-yl)nicotinonitrile(Compound 534)

1H NMR (CHLOROFORM-d) δ8.37 (d, J=5.3 Hz, 1H), 7.97 (s, 1H), 6.89 (d,J=5.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.51 (d, J=12.8 Hz, 1H),4.00-4.17 (m, 1H), 3.68-3.87 (m, 1H), 3.17-3.38 (m, 3H), 3.12 (d, J=11.8Hz, 1H), 2.82 (s, 2H), 2.33-2.45 (m, 1H), 1.35 (br. s., 1H), 1.18-1.25(m, 2H), 0.98-1.10 (m, 2H), 0.64 (br. s., 1H), 0.57 (br. s., 1H),0.38-0.54 (m, 2H). LC-MS: m/z 472.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-(2-hydroxyethylamino)pyrimidin-4-yl)nicotinonitrile(Compound 512)

Synthesized according to the procedure described in Compound 507 exceptusing 2-(methylamino)ethanol instead of NH₃.EtOH. ¹H NMR (CHLOROFORM-d)δ 8.32 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 6.83 (d, J=5.3 Hz, 1H), 5.91(br. s., 1H), 4.63 (d, J=12.8 Hz, 1H), 4.50 (d, J=12.5 Hz, 1H),3.96-4.33 (m, 1H), 3.82-3.92 (m, 2H), 3.63-3.72 (m, 2H), 3.29 (br. s.,1H), 3.14 (br. s., 1H), 2.68-2.78 (m, 1H), 2.66 (br. s., 1H), 2.34-2.44(m, 1H), 1.20-1.35 (m, 4H), 1.04 (dd, J=7.7, 3.4 Hz, 4H), 0.77-0.90 (m,3H), 0.64 (br. s., 1H), 0.49-0.55 (m, 1H), 0.44 (dt, J=9.3, 4.4 Hz, 1H).LC-MS: m/z 474.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(2-(dimethylamino)pyrimidin-4-yl)nicotinonitrile(Compound 521)

1H NMR (CHLOROFORM-d) δ 8.42 (d, J=5.3 Hz, 1H), 8.00 (s, 1H), 6.75 (d,J=5.3 Hz, 1H), 4.62 (d, J=13.1 Hz, 1H), 4.50 (d, J=12.8 Hz, 1H),3.96-4.20 (m, 1H), 3.68-3.96 (m, 1H), 3.28-3.42 (m, 2H), 3.09-3.15 (m,1H), 2.42-2.54 (m, 1H), 1.39-1.56 (m, 1H), 1.14-1.25 (m, 2H), 0.98-1.08(m, 2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H), 0.43-0.53 (m, 2H). LC-MS:m/z 500.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyrazin-2-yl)nicotinonitrile(Compound 515)

Step 1

To a flask was added with(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(70 mg, 0.151 mmol), 2,6-dichloropyrazine (30 mg, 0.197 mmol), Pd(PPh₃)₄(17 mg, 0.015 mmol), K₂CO₃ (63 mg, 0.453 mmol), and 1.5 mL DMF. Themixture was stirred at 120° C. for 2 h. After washing with Satd. NaHCO3,brine, the combined organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo. Prep-TLC purification (20% EtOAc/petroleum ether)afforded 25 mgof(R)-5-(6-chloropyrazin-2-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile.

Step 2

To a flask was added with(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyrazin-2-yl)nicotinonitrile(18 mg 0.04 mmol), tributyl(vinyl)stannane (17 mg, 0.052 mmol),Pd(PPh₃)₄(5 mg, 0.004 mmol), K₂CO₃ (14 mg, 0.052 mmol), and 1.5 mL DMF.The mixture was stirred at 120° C. for 2 h. After washing with Satd.NaHCO₃, brine, the combined organic layer was dried over anhy. Na₂SO₄and concentrated in vacuo. Prep-TLC purification (20% EtOAc/petroleumether) afforded 10 mg of title compound. ¹H NMR (CHLOROFORM-d) δ 8.72(s, 1H), 8.56 (s, 1H), 8.00 (s, 1H), 6.90 (dd, J=17.3, 10.8 Hz, 1H),6.47 (dd, J=17.6, 1.0 Hz, 1H), 5.70 (dd, J=10.8, 1.0 Hz, 1H), 4.65 (d,J=13.1 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.99-4.29 (m, 1H), 3.52-3.91(m, 1H), 3.32 (br. s., 1H), 3.16 (br. s., 1H), 2.22-2.35 (m, 1H),1.23-1.38 (m, 5H), 0.97-1.14 (m, 4H), 0.81 (dd, J=7.8, 2.3 Hz, 2H), 0.65(br. s., 1H), 0.48-0.55 (m, 1H), 0.45 (dt, J=9.6, 4.6 Hz, 1H).

LC-MS: m/z 441.2 (M+H)⁺

(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 530; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.61 (d, J=5.0 Hz, 1H), 7.55-7.68 (m, 1H), 7.36(s, 1H), 7.21 (dd, J=10, 1.5 Hz, 1H), 6.84 (dd, J=17.6, 10.8 Hz, 1H),6.17-6.35 (m, 1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.53 (d, J=12.5 Hz,1H), 4.32-4.47 (m, 1H), 4.01-4.16 (m, 0.5H), 3.86 (d, J=12.5 Hz, 0.5H),3.70 (t, J=5.5 Hz, 3H), 3.35 (s, 3H), 3.18 (d, J=11.3 Hz, 2H), 2.94-3.14(m, 1H), 2.56-2.73 (m, 2H), 1.90-2.10 (m, 1H), 1.22-1.34 (m, 1H),1.14-1.32 (m, 2H), 0.83-1.06 (m, 2H), 0.58 (br. s., 1H), 0.52 (br. s.,1H), 0.28-0.48 (m, 2H). LC-MS: m/z 458.2 (M+H)⁺

(R)-6-(4-acetyl-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 562; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.5 Hz, 1H), 7.65 (s, 1H), 7.39 (s,1H), 7.24 (d, J=4.0 Hz, 1H), 6.88 (dd, J=17.3, 10.8 Hz, 1H), 6.28 (d,J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.65 (br. s., 0.5H), 4.55 (d,J=12.5 Hz, 1H), 4.43 (d, J=12.0 Hz, 1H), 4.08 (br. s., 0.5H), 3.77 (br.s., 1H), 3.21 (br. s., 2H), 3.11 (br. s., 1H), 2.17 (br. s., 2H), 2.11(br. s., 1H), 2.03 (br. s., 1H), 1.28 (d, J=12.0 Hz, 2H), 1.24-1.50 (br.s., 3H), 0.60 (br. s., 2H), 0.45 (br. s., 2H). LC-MS: m/z 414.3 (M+H)⁺

(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxy-3-methylbutanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 561; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.66 (s, 1H), 7.39 (s,1H), 7.24 (d, J=4.0 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H), 6.28 (d,J=17.6 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 5.16 (br. s., 1H), 4.56 (d,J=13.1 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.14 (d, J=8.8 Hz, 0.5H),3.65-3.78 (m, 1H), 3.17-3.91 (m, 1.5H), 3.04-3.14 (m, 1H), 2.43-2.57 (m,2H), 2.02-2.07 (m, 1H), 1.33 (s, 6H), 1.25-1.30 (m, 2H), 1.21 (br. s.,2H), 1.02 (dd, J=7.5, 3.3 Hz, 2H), 0.65 (d, J=6.5 Hz, 1H), 0.42-0.53 (m,2H). LC-MS: m/z 472.3 (M+H)⁺

(R)-2-cyclopropyl-6-(4-(2-ethoxyacetyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 573; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.65 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.36-7.41(m, 1H), 7.23 (dd, J=5.0, 1.8 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H),6.21-6.35 (m, 1H), 5.57 (dd, J=10.9, 0.9 Hz, 1H), 4.84 (br. s., 0.5H),4.35 (br. s., 2H), 4.27 (br. s., 1H), 4.20 (br. s., 2H), 3.89 (br. s.,0.5H), 3.53-3.65 (m, 2.5H), 3.24-3.35 (m, 1H), 3.17 (br. s., 1.5H),1.98-2.08 (m, 1H), 1.29-1.41 (m, 3H), 1.23-1.28 (m, 3H), 1.15-1.23 (m,2H), 0.95-1.07 (m, 2H). LC-MS: m/z 432.2 (M+H)⁺

(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 590; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.63 (d, J=5.0 Hz, 1H), 7.53-7.75 (m, 2H), 7.37(s, 1H), 7.22 (dd, J=4.8, 1.5 Hz, 1H), 6.86 (dd, J=17.6, 10.8 Hz, 1H),6.19-6.37 (m, 1H), 5.54 (d, J=11.5 Hz, 1H), 4.55 (d, J=13.1 Hz, 1H),4.42 (d, J=12.8 Hz, 1H), 4.11-4.17 (m, 2H), 3.44 (s, 4H), 3.19-3.25 (m,1H), 3.04-3.11 (m, 1H), 2.80 (s, 1H), 1.89-2.07 (m, 2H), 1.17-1.27 (m,4H), 0.95-1.02 (m, 2H), 0.41-0.54 (m, 3H). LC-MS: m/z 444.2 (M+H)⁺

2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 572; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.61-7.69 (m, 1H),7.36-7.44 (m, 1H), 7.24 (dd, J=5.0, 1.8 Hz, 1H), 6.89 (dd, J=17.3, 10.8Hz, 1H), 6.29 (dd, J=17.6, 1.0 Hz, 1H), 5.58 (dd, J=10.8, 0.8 Hz, 1H),4.90 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.26-4.40 (m, 2H),4.12-4.23 (m, 1H), 3.93 (br. s., 2H), 3.74 (d, J=13.1 Hz, 1H), 3.29-3.34(m, 1H), 3.06-3.18 (m, 1H), 2.50-2.63 (m, 1H), 2.17-2.25 (m, 1H),2.02-2.07 (m, 1H), 1.41 (d, J=6.8 Hz, 1H), 1.29-1.33 (m, 2H), 1.28 (d,J=2.8 Hz, 1H), 1.19-1.22 (m, 1.5H), 1.02 (dd, J=7.9, 3.1 Hz, 1.5H).LC-MS: m/z 418.2 (M+H)⁺

(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(furan-3-carbonyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 546; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.5 Hz, 1H), 7.73 (s, 1H), 7.65 (s,1H), 7.46 (s, 1H), 7.36-7.44 (m, 1H), 7.25 (d, J=4.3 Hz, 1H), 6.88 (dd,J=17.4, 10.9 Hz, 1H), 6.56 (s, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.56 (d,J=10.8 Hz, 1H), 4.60 (d, J=13.1 Hz, 1H), 4.44 (d, J=12.8 Hz, 1H), 4.27(br. s., 1H), 3.93 (br. s., 1H), 3.66 (br. s., 1H), 3.19-3.38 (m, 1H),3.09 (t, J=11.3 Hz, 1H), 2.03 (dd, J=7.4, 3.1 Hz, 1H), 1.35-1.50 (m,1H), 1.13-1.35 (m, 2H), 0.90-1.08 (m, 2H), 0.59-0.76 (m, 1H), 0.52 (t,J=8.0 Hz, 1H), 0.42 (br. s., 2H). LC-MS: m/z 466.2 (M+H)⁺

2-cyclopropyl-6-((R)-3-cyclopropyl-4-((S)-3-hydroxybutanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 595; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.39 (s,1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d,J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.43 (d,J=12.5 Hz, 1H), 4.17-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.79 (br. s., 1H),3.71 (d, J=11.8 Hz, 1H), 3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48(m, 1H), 2.04 (m, 1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br.s., 1H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H). LC-MS:m/z 458.2 (M+H)⁺

(R)-2-cyclopropyl-6-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 631; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ ¹H NMR (CHLOROFORM-d) v 8.61 (d, J=5.0 Hz, 1H),7.60 (d, J=2.5 Hz, 1H), 7.20 (dd, J=5.0, 1.5 Hz, 1H), 6.84 (dd, J=17.3,10.8 Hz, 1H), 6.25 (d, J=17.6 Hz, 1H), 5.52 (d, J=11.0 Hz, 1H),4.50-4.79 (m, 2H), 4.28-4.50 (m, 2H), 3.85 (d, J=13.6 Hz, 1H), 3.63-3.79(m, 2H), 3.57 (d, J=10.0 Hz, 1H), 3.30-3.49 (m, 3H), 2.99-3.27 (m, 2H),2.83-2.98 (m, 1H), 2.49-2.79 (m, 1H), 2.17 (dt, J=10.5, 6.7 Hz, 1H),1.08-1.30 (m, 3H), 0.78-1.08 (m, 7H). LC-MS: m/z 460.1 (M+H)⁺

(R)-2-cyclopropyl-6-(4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 632; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.31-7.50(m, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.87 (dd, J=17.4, 10.9 Hz, 1H),6.27 (dd, J=17.4, 0.9 Hz, 1H), 5.42-5.72 (m, 1H), 4.84 (br. s., 1H),4.20-4.40 (m, 3H), 4.00-4.20 (m, 1H), 3.36-3.65 (m, 2H), 3.20-3.36 (m,2H), 2.97-3.20 (m, 1H), 2.70-2.96 (m, 4H), 1.86-2.06 (m, 1H), 1.40 (d,J=6.3 Hz, 1H), 1.09-1.36 (m, 4H), 0.79-1.09 (m, 2H). LC-MS: m/z 404.0(M+H)⁺

2-cyclopropyl-6-((R)-3-cyclopropyl-4-((R)-3-hydroxybutanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 585; General procedure 5, Step W)

1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.39 (s,1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d,J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.43 (d,J=12.5 Hz, 1H), 4.17-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.79 (br. s., 1H),3.71 (d, J=11.8 Hz, 1H), 3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48(m, 1H), 2.04 (m, 1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br.s., 1H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H). LC-MS:m/z 458.2 (M+H)⁺

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)nicotinonitrile(Compound 539; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 10.76 (br. s., 1H), 8.37 (br. s., 1H), 8.00 (s,1H), 7.65-7.77 (m, 1H), 7.48 (d, J=3.3 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H),4.71 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 1H), 4.41 (d, J=12.5 Hz, 1H),4.14 (d, J=7.3 Hz, 0.5H), 3.66-3.95 (m, 1.5H), 3.15-3.44 (m, 4.5H), 2.40(br. s., 1H), 2.05-2.15 (m, 1H), 1.39-1.48 (m, 1H), 1.17-1.25 (m, 2H),0.94-1.04 (m, 2H), 0.44-0.81 (m, 4H). LC-MS: m/z 495.3 (M+H)⁺

6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl)piperazin-1-yl)-5-(4-fluorophenyl)nicotinonitrile(Compound 548; General procedure 3, Step R and S)

¹H NMR (CHLOROFORM-d) δ 7.58-7.63 (m, 1H), 7.33-7.43 (m, 2H), 7.09-7.21(m, 2H), 4.39-4.50 (m, 2.5H), 4.05-4.13 (m, 1H), 3.82 (br. s., 0.5H),3.50-3.72 (m, 4H), 2.97-3.29 (m, 3H), 1.99-2.06 (m, 1H), 1.84-1.96 (m,1H), 1.14-1.27 (m, 7H), 0.93-1.00 (m, 2H), 0.38-0.72 (m, 4H). LC-MS: m/z475.3 (M+H)⁺

(R)-5-(2-chloroquinolin-5-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 549)

1H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (d, J=8.5 Hz, 1H), 7.91 (dd,J=11.4, 8.9 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.46-7.57 (m,1H), 7.39 (d, J=8.8 Hz, 1H), 4.78 (dq, J=13.5, 6.8 Hz, 0.5H), 4.57 (d,J=11.8 Hz, 1.5H), 4.45 (d, J=11.0 Hz, 1H), 3.92-4.07 (m, 0.5H),3.57-3.76 (m, 0.5H), 3.40 (q, J=7.0 Hz, 1H), 3.18-3.35 (m, 2H),1.65-1.82 (m, 1H), 1.20-1.31 (m, 4H), 1.07-1.20 (m, 2H), 0.64-0.91 (m,4H), 0.38-0.60 (m, 4H). LC-MS: m/z 498.2 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(4-fluorophenyl)nicotinonitrile(Compound 550)

1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.33-7.43 (m, 2H), 7.09-7.20 (m,2H), 4.55 (br. s., 1H), 4.47 (br. s., 1H), 4.25 (d, J=13.1 Hz, 3H), 3.40(br. s., 1H), 3.31 (br. s., 1H), 3.15 (br. s., 1H), 1.95-2.10 (m, 1H),1.77 (br. s., 2H), 1.64 (br. s., 2H), 1.39-1.53 (m, 2H), 1.34 (br. s.,2H), 0.90-1.12 (m, 5H), 0.69-0.90 (m, 2H). LC-MS: m/z 405.2 (M+H)⁺

6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1R,2S)-2-ethoxycyclopropanecarbonyl)piperazin-1-yl)-5-(4-fluorophenyllnicotinonitrile(Compound 564)

¹H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.33-7.41 (m, 2H), 7.15 (t, J=8.7Hz, 2H), 4.69-4.72 (m, 0.5H), 4.31-4.58 (m, 2H), 4.20 (d, J=13.8 Hz,1H), 3.16-3.82 (m, 7.5H), 1.98-2.09 (m, 1H), 1.77-1.90 (m, 1H),1.08-1.32 (m, 7H), 0.86-1.08 (m, 2H), 0.31-0.62 (m, 4H). LC-MS: m/z475.3 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile(Compound 556; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.52 (br. s., 1H), 8.07 (d,J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 7.65-7.69 (m, 1H), 7.63 (s, 1H), 7.47(t, J=5.6 Hz, 1H), 4.89-5.55 (m, 3H), 4.15-4.58 (m, 4H), 1.56-1.68 (m,1H), 1.42-1.56 (m, 1H), 1.12-1.21 (m, 2H), 0.97-1.09 (m, 4H), 0.75-0.96(m, 6H). LC-MS: m/z 438.3 (M+H)⁺

(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 575; General procedure 1, Step I)

1H NMR (CHLOROFORM-d) δ 7.49 (s, 1H), 6.47-6.77 (m, 1H), 6.22-6.44 (m,1H), 5.88 (br. s., 1H), 5.76 (d, J=10.0 Hz, 1H), 3.01-4.86 (m, 11H),2.40 (br. s., 2H), 1.95-2.16 (m, 1H), 1.76 (br. s., 1H), 1.29-1.38 (m,3H), 1.08-1.19 (m, 2H), 0.92-1.08 (m, 4H), 0.71-0.86 (m, 2H). LC-MS: m/z448.0 (M+H)⁺

5-(1-acryloylpiperidin-3-yl)-2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile(Compound 576; General procedure 1, Step I)

1H NMR (CHLOROFORM-d) δ 7.51-7.57 (m, 1H), 6.53-6.73 (m, 1H), 6.25-6.41(m, 1H), 5.65-5.80 (m, 1H), 4.02-5.02 (m, 6H), 2.94-4.00 (m, 5H),2.37-2.49 (m, 1H), 2.28-2.37 (m, 1H), 1.92-2.13 (m, 1H), 1.57-1.80 (m,6H), 0.96-1.22 (m, 6H), 0.69-0.88 (m, 2H). LC-MS: m/z 448.2 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-3,3′-bipyridine-5,6′-dicarbonitrile(Compound 583; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.80 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.0, 2.3 Hz,1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 4.09-4.85 (m, 4H), 3.22-3.64(m, 3H), 1.82-1.93 (m, 1H), 1.75 (br. s., 1H), 1.19-1.27 (m, 2H),0.96-1.12 (m, 4H), 0.73-0.92 (m, 2H). LC-MS: m/z 413.2 (M+H)⁺

(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,3′-bipyridine-5,6′-dicarbonitrile(Compound 584; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) 8.79 (d, J=1.5 Hz, 1H), 7.90 (dd, J=8.0, 2.3 Hz,1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 4.89 (br. s., 0.5H), 4.52 (d,J=9.8 Hz, 0.5H), 4.19-4.44 (m, 2.5H), 3.65-3.78 (m, 2.5H), 3.54 (t,J=11.0 Hz, 0.5H), 3.28-3.43 (m, 4H), 3.03-3.27 (m, 1.5H), 2.50-2.80 (m,2H), 1.82-1.92 (m, 1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.23-1.28 (m, 1.5H),1.17-1.23 (m, 2H), 0.94-1.06 (m, 2H); LC-MS: m/z 431.2 (M+H)

(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-2′-ethynyl-3,4′-bipyridine-5-carbonitrile(Compound 593; General procedure 1, Step H)

1H NMR (CHLOROFORM-d) δ 8.67 (d, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.46-7.59(m, 1H), 7.35 (dd, J=5.1, 1.6 Hz, 1H), 4.15-4.90 (m, 4H), 3.13-3.75 (m,4H), 1.94-2.04 (m, 1H), 1.76 (br. s., 1H), 1.28-1.39 (m, 3H), 1.21 (dt,J=7.0, 3.5 Hz, 2H), 0.95-1.09 (m, 4H), 0.76-0.88 (m, 2H). LC-MS: m/z413.9 (M+H)⁺

(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(1-propioloyl-1,2,5,6-tetrahydropyridin-3-yl)nicotinonitrile(Compound 594; General procedure 1, Step H)

1H NMR (CHLOROFORM-d) δ 7.48 (d, J=5.5 Hz, 1H), 5.90 (d, J=11.3 Hz, 1H),4.01-4.85 (m, 7), 3.96 (t, J=5.9 Hz, 1H), 3.82 (t, J=5.9 Hz, 1H),3.03-3.80 (m, 4H), 2.82 (s, 1H), 2.44 (d, J=3.5 Hz, 1H), 2.38 (d, J=3.5Hz, 1H), 2.06-2.12 (m, 1H), 1.31-1.37 (m, 3H), 0.97-1.17 (m, 6H), 0.81(d, J=7.8 Hz, 2H). LC-MS: m/z 444.1 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-3′-fluoro-2′-vinyl-3,4′-bipyridine-5-carbonitrile(Compound 520; General procedure 1, Step I)

¹H NMR (CHLOROFORM-d) δ 8.46 (d, J=4.8 Hz, 1H), 7.64 (s, 1H), 7.19 (t,J=5.1 Hz, 1H), 7.08 (ddd, J=17.4, 11.0, 1.3 Hz, 1H), 6.51 (dd, J=17.3,1.8 Hz, 1H), 5.66 (dd, J=10.9, 1.6 Hz, 1H), 4.59 (d, J=12.8 Hz, 1H),4.47 (d, J=12.5 Hz, 1H), 4.22 (br. s., 0.5H), 4.05 (br. s., 0.5H), 3.76(dt, J=8.2, 4.0 Hz, 1H), 3.47-3.70 (m, 1H), 3.29 (br. s., 1H), 3.14 (br.s., 1H), 1.77-1.85 (m, 1H), 1.57-1.70 (m, 1H), 1.32-1.41 (m, 1H),1.14-1.24 (m, 2H), 0.88-1.11 (m, 4H), 0.73-0.86 (m, 2H), 0.59-0.73 (m,1H), 0.36-0.59 (m, 3H). LC-MS: m/z 458.5 (M+H)⁺

6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile(Compound 514; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (dd, J=5.9, 1.9 Hz, 1H), 8.07(d, J=8.0 Hz, 1H), 7.69-7.75 (m, 1H), 7.64-7.68 (m, 2H), 7.44 (dd,J=12.5, 6.0 Hz, 1H), 4.46-4.59 (m, 2.5H), 4.08-4.18 (m, 1H), 3.86 (br.s., 0.5H), 3.53-3.74 (m, 3H), 3.21-3.32 (m, 2H), 1.87-2.06 (m, 2H),1.49-1.58 (m, 1H), 1.33 (d, J=5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.81-0.90(m, 2H), 0.65 (br. s., 1H), 0.36-0.59 (m, 3H). LC-MS: m/z 508.2 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-3,4′-bipyridine-2′,5-dicarbonitrile(Compound 522; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) δ 8.81 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.63 (s,1H), 7.59 (dd, J=5.1, 1.6 Hz, 1H), 4.86 (br. s., 1H), 4.48 (br. s., 1H),4.35 (d, J=13.6 Hz, 2H), 3.63 (br. s., 0.5H), 3.53 (br. s., 1H), 3.25(br. s., 1.5H), 1.85-1.99 (m, 1H), 1.76 (br. s., 1H), 1.60 (br. s., 3H),1.17-1.34 (m, 4H), 1.07 (dd, J=7.8, 3.0 Hz, 4H). LC-MS: m/z 413.5 (M+H)⁺

(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-2′-methyl-3,4′-bipyridine-5-carbonitrile(Compound 523; General procedure 1, Step H)

¹H NMR (CHLOROFORM-d) 8.56 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.21 (s,1H), 7.17 (d, J=5.3 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.44 (d, J=12.3Hz, 1H), 4.04 (br. s., 1H), 3.75 (br. s., 1.5H), 3.28 (br. s., 1.5H),3.12 (br. s., 1H), 2.58-2.68 (m, 3H), 1.97-2.07 (m, 1H), 1.72 (br. s.,1H), 1.37 (br. s., 1H), 1.14-1.23 (m, 2H), 0.93-1.10 (m, 4H), 0.74-0.85(m, 2H), 0.65 (br. s., 1H), 0.36-0.58 (m, 3H). LC-MS: m/z 428.5 (M+H)⁺

(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-[3,3′-bipyridine]-5,5′-dicarbonitrile(Compound 525; General procedure 2, Step M)

¹H NMR (CHLOROFORM-d) δ8.90 (d, 2H), 8.04 (s, 1H), 7.64 (s, 1H), 4.63(d, J=13.1 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.13 (br. s., 1H), 3.78(br. s., 1H), 3.51 (s, 1H), 3.33 (d, J=9.0 Hz, 2H), 3.24 (d, J=12.5 Hz,1H), 3.15 (d, J=12.3 Hz, 1H), 2.03 (dt, J=15.3, 7.4 Hz, 1H), 1.01-1.12(m, 3H), 0.82-0.95 (m, 4H), 0.66 (br. s., 1H), 0.45-0.53 (m, 1H)

LC-MS: m/z 481.4 (M+H)⁺

Compound 540 (General Procedure 2, Step M)(R)-5′-cyano-2′-cyclopropyl-6′-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-[3,3′-bipyridine]-5-carboxamide

¹H NMR (METHANOL-d) δ9.05 (br. s., 1H), 8.81 (br. s., 1H), 8.26 (t,J=2.1 Hz, 1H), 7.60-7.77 (m, 1H), 6.81 (br. s., 1H), 6.25 (br. s., 1H),4.57 (d, J=13.1 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 4.01-4.25 (m, 1H),3.65-3.88 (m, 2H), 3.12-3.38 (m, 4H), 2.03-2.24 (m, 1H), 1.86-1.96 (m,1H), 1.15-1.28 (m, 4H), 0.97-1.06 (m, 2H), 0.28-0.58 (m, 4H)

LC-MS: m/z 499.5 (M+H)⁺

Compound 554 (General Procedure, Step I)(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-5′-(1H-tetrazol-5-yl)-[3,3′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ9.47 (br. s., 1H), 8.86 (s, 1H), 8.62 (s, 1H),7.73 (s, 1H), 4.59-4.47 (m., 7H), 1.19-1.30 (m, 1H), 1.14-1.05 (m, 3H),0.84-0.98 (m, 10H), 0.42-0.57 (m, 4H)

LC-MS: m/z 482.5 (M+H)⁺

Compound 601 (General Procedure, Step I)(R)-6-cyclopropyl-5-(5-fluoro-4-vinylpyrimidin-2-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ8.62 (d, J=1.8 Hz, 1H), 8.35-8.44 (m, 1H), 7.03(dd, J=17.3, 10.8 Hz, 1H), 6.70-6.82 (m, 1H), 5.81-5.92 (m, 1H), 4.90(br. s., 0.5H), 4.52 (m, 3.5H), 4.28-4.47 (m, 3H), 3.68-3.86 (m, 3H),3.54 (br. s., 1H), 3.01-3.21 (m, 3H), 2.63-2.79 (m, 1H), 2.51-2.63 (m,1H), 1.23-1.26 (m, 4H), 1.18-1.23 (m, 2H), 1.04 (m, 2H)

LC-MS: m/z 451.5 (M+H)⁺

Compound 538 (General Procedure 1, Step I)(R)-5-(2-aminoquinazolin-5-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.82 (d, J=9.5 Hz, 1H), 7.70-7.84 (m, 1H),7.55-7.70 (m, 2H), 7.11-7.23 (m, 1H), 5.52 (br. s., 2H), 4.39-4.67 (m,2.5H), 4.16-4.32 (m, 1H), 3.60-3.85 (m, 1H), 3.10-3.41 (m, 2.5H), 1.73(s, 1H), 1.53-1.65 (m, 1H), 1.27-1.33 (m, 1H), 1.18-1.24 (m, 1H),1.11-1.18 (m, 1H), 0.98-1.10 (m, 2H), 0.79-0.90 (m, 4H), 0.61-0.74 (m,1H), 0.40-0.61 (m, 3H)

LC-MS: m/z 480.2 (M+H)⁺

Compound 567 (General Procedure 1, Step H)(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-6′-(trifluoromethyl)-[3,3′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.83 (d, J=1.8 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz,1H), 7.77-7.87 (m, 1H), 7.65 (s, 1H), 4.40-4.72 (m, 2.5H), 3.97-4.20 (m,1H), 3.51-3.78 (m, 1H), 3.08-3.62 (m, 2.5H), 1.86-1.98 (m, 1H), 1.72 (s,1H), 1.34-1.45 (m, 1H), 1.20-1.28 (m, 2H), 0.97-1.10 (m, 4H), 0.76-0.87(m, 2H), 0.40-0.67 (m, 3H)

LC-MS: m/z 482.2 (M+H)⁺

Compound 586 (General Procedure 1, Step H)(R)-2,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.34 (s, 2H), 4.91 (s, 0.5H),4.50-4.56 (m, 0.5H), 4.22-4.50 (m, 2.5H), 3.68-3.89 (m, 2.5H), 3.49-3.62(m, 0.5H), 3.28-3.43 (m, 4H), 3.06-3.27 (m, 1.5H), 2.64-2.83 (m, 1H),2.55-2.64 (m, 1H), 1.92-2.01 (m, 1H), 1.37 (d, J=6.5 Hz, 2H), 1.21-1.31(m, 3H), 1.01-1.12 (m, 2H)

LC-MS: m/z 474.1 (M+H)⁺

Compounnd 622(R)-2-cyclopropyl-2′-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-6′-vinyl-[3,4′-bipyridine]-5-carbonitrile

The mixture of(R)-2′-chloro-2-cyclopropyl-6′-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile(40 mg, 0.085 mmol), Potassium vinyltrifluoroborate (18 mg, 0.128 mmol),Pd(dppf)Cl₂ (4 mg, 0.0043 mmol), CsF (39 mg, 0.255 mmol) in dioxane/H₂Owas stirred at 100° C. for 16 hours, the mixture was partitioned betweenEtOAc and water, the organic was washed with water, brine andconcentrated to give the crude which was purified by column to give 15mg of the product.

¹H NMR (CHLOROFORM-d) 7.60 (s, 1H), 6.86 (d, J=1.0 Hz, 1H), 6.75 (dd,J=17.1, 10.5 Hz, 1H), 6.66 (d, J=1.0 Hz, 1H), 6.36 (dd, J=17.2, 1.6 Hz,1H), 5.49 (dd, J=10.5, 1.8 Hz, 1H), 4.90 (s, 0.5H), 4.53 (d, J=13.3 Hz,0.5H), 4.22-4.38 (m, 2.5H), 4.02 (s, 3H), 3.78-3.84 (m, 0.5H), 3.75 (t,J=6.1 Hz, 2H), 3.51-3.58 (m, 0.5H), 3.38 (s, 3H), 3.28 (t, J=9.9 Hz,1H), 3.00-3.19 (m, 1.5H), 2.65-2.79 (m, 1H), 2.54-2.64 (m, 1H) 2.03-2.10(m, 1H), 1.38 (d, J=6.3 Hz, 1H), 1.28 (d, J=6.8 Hz, 2H), 1.13-1.21 (m,2H), 0.94-1.03 (m, 2H)

LC-MS: m/z 461.2 (M+H)⁺

Compound 623(R)-2′-chloro-2-cyclopropyl-6′-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile

To a solution of(R)-2′,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile(300 mg, 0.623 mmol) MeOH was added NaOMe (69 mg, 1.26 mmol), themixture was refluxed for 16 hours. After cooling, the mixture waspartitioned between EtOAc and water, the organic layer was washed withwater, brine and dried over Na₂SO₄. The organic layer was concentratedto give the crude which was purified by prep-HPLC to obtained 150 mg ofthe product.

¹H NMR (CHLOROFORM-d) 7.54-7.63 (m, 1H), 6.97 (d, J=1.3 Hz, 1H), 6.70(d, J=1.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d, J=12.8 Hz, 0.5H), 4.23-4.39(m, 2.5H), 3.96 (s, 3H), 3.79-3.85 (m, 0.5H), 3.68-3.78 (m, 2H),3.49-3.60 (m, 0.5H), 3.39 (s, 3H), 3.26-3.36 (m, 1H), 3.04-3.20 (m,1.5H), 2.64-2.82 (m, 1H), 2.50-2.63 (m, 1H), 2.00-2.04 (m, 1), 1.38 (d,J=6.5 Hz, 1H), 1.28 (d, J=5.5 Hz, 2H), 1.13-1.21 (m, 2H), 0.97-1.06 (m,2H)

LC-MS: m/z 470.2 (M+H)⁺

Compound 624(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2′,6′-divinyl-[3,4′-bipyridine]-5-carbonitrile

The mixture of(R)-2′,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile(50 mg, 0.105 mmol), Potassium vinyltrifluoroborate (50 mg, 0.316 mmol),Pd(dppf)Cl₂ (4 mg, 0.0043 mmol), CsF (50 mg, 0.316 mmol) in dioxane/H₂Owas stirred at 100° C. for 16 hours, the mixture was partitioned betweenEtOAc and water, the organic was washed with water, brine andconcentrated to give the crude which was purified by column to give 25mg of the product.

¹H NMR (CHLOROFORM-d) 7.63 (s, 1H), 7.24 (s, 1H), 7.28 (s, 1H),6.77-6.98 (m, 2H), 6.30 (s, 1H), 6.34 (s, 1H), 5.55 (d, J=10.8 Hz, 2H),4.09 (s, 0.5H), 4.53 (d, J=12.3 Hz, 0.5H), 4.21-4.36 (m, 2.5H),3.68-3.85 (m, 3H), 3.50-3.61 (m, 0.5H), 3.38 (s, 4H), 3.03-3.15 (m, 1H),2.70 (dd, J=15.7, 6.4 Hz, 1H), 2.51-2.59 (m, 1H), 1.90-2.12 (m, 1H),1.36-1.42 (m, 1H), 1.22-1.30 (m, 2H), 1.18 (s, 2H), 0.94-1.05 (m, 2H)

LC-MS: m/z 458.2 (M+H)⁺

Compound 634 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.15 (d, J=11.3 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H),7.93 (t, J=7.8 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.50 (dd, J=10.3, 7.3Hz, 1H), 7.04 (dd, J=17.2, 10.7 Hz, 1H), 6.78 (d, J=17.1 Hz, 1H), 5.85(d, J=10.5 Hz, 1H), 4.64-4.76 (m, 1H), 4.42-4.49 (m, 1H), 3.88 (d,J=13.6 Hz, 0.5H), 3.73 (d, J=5.8 Hz, 2H), 3.61 (d, J=9.8 Hz, 0.5H),3.39-3.50 (m, 0.5H), 3.37 (s, 3H), 3.05-3.25 (m, 2H), 2.85-3.10 (m,0.5H), 2.50-2.85 (m, 2H), 2.18-2.33 (m, 1H), 1.99-2.15 (m, 1H),0.99-1.22 (m, 6H), 0.82-0.94 (m, 5H)

LC-MS: m/z 511.3 (M+H)⁺

Compound 635 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.15 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H),7.94 (t, J=7.8 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.43-7.56 (m, 1H), 7.04(dd, J=17.3, 10.5 Hz, 1H), 6.78 (d, J=17.1 Hz, 1H), 5.85 (d, J=10.5 Hz,1H), 4.33-4.80 (m, 2.5H), 4.07-4.22 (m, 0.5H), 3.85-4.02 (m, 1H),3.60-3.81 (m, 3H), 3.37 (s, 3H), 2.98-3.26 (m, 2H), 2.37-2.76 (m, 2H),1.98-2.28 (m, 1H), 1.51-1.61 (m, 1H), 1.11-1.26 (m, 2H), 0.86 (d, J=7.8Hz, 2H), 0.40-0.55 (m, 4H)

LC-MS: m/z 509.3 (M+H)⁺

Compound 636 (General Procedure 1, Step I)(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinylquinazolin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.16 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H),7.94 (t, J=7.8 Hz, 1H), 7.62-7.72 (m, 1H), 7.44-7.56 (m, 1H), 7.05 (dd,J=17.3, 10.5 Hz, 1H), 6.78 (d, J=17.1 Hz, 1H), 5.75-5.95 (m, 1H),4.49-4.66 (m, 2.5H), 4.05-4.25 (m, 1H), 3.75-3.88 (m, 1H), 3.06-3.32 (m,2.5H), 2.29 (s, 1H), 1.50-1.57 (m, 1H), 1.34-1.47 (m, 1H), 1.14-1.22 (m,2H), 0.98-1.09 (m, 2H), 0.77-0.91 (m, 4H), 0.39-0.67 (m, 4H)

LC-MS: m/z 491.2 (M+H)⁺

Compound 645 (General procedure 1, Step I)

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile(Core synthesis method 1 using 4-chloro-2-vinyl-1,8-naphthyridine asstarting material)

In a sealed tube was added 120 mg of 4-chloro-2-vinyl-1,8-naphthyridine,242 mg of 8-3 (0.5 mmol), 230 mg of CsF (1.5 mmol), 41 mg ofPd(dppf)₂Cl₂ (0.05 mmol) and 10 mL of Dioxane, then the mixture washeated in a microwave reactor (100° C., 30 minutes), when LC-MSindicated the product formation. Then the resulting mixture wasfiltered, the filtrated was concentrated, purified by Prep-TLC(Petroleum ether:Ethyl acetate=2:1) to give 45 mg of title compound. ¹HNMR (CHLOROFORM-d) δ 9.17 (dd, J=4.3, 1.8 Hz, 1H), 8.03 (td, J=8.7, 1.8Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.48 (dd,J=8.3, 4.3 Hz, 1H), 7.15 (dd, J=17.7, 10.9 Hz, 1H), 6.57 (dd, J=17.6,1.8 Hz, 1H), 5.83 (d, J=11.0 Hz, 1H), 4.60 (d, J=12.3 Hz, 2H), 4.49 (d,J=12.8 Hz, 1H), 4.15 (br. s., 0.5H), 3.91 (br. s., 0.5H), 3.65-3.85 (m,3H), 3.40 (s, 4H), 3.27 (d, J=12.0 Hz, 2H), 2.67 (br. s., 2H), 1.20 (d,J=4.5 Hz, 2H), 0.82-0.98 (m, 2H), 0.66 (br. s., 1H), 0.59 (br. s., 1H),0.49 (d, J=5.0 Hz, 2H)

LC-MS: m/z 509.1 (M+H)⁺

Compound 629 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.99-9.21 (m, 1H), 7.99 (dd, J=12.4, 8.4 Hz,1H), 7.50-7.72 (m, 2H), 7.45 (dt, J=7.8, 3.7 Hz, 1H), 7.11 (dd, J=17.4,10.9 Hz, 1H), 6.53 (d, J=17.6 Hz, 1H), 5.79 (d, J=10.8 Hz, 1H),4.56-4.78 (m, 1.5H), 4.35-4.56 (m, 2H), 3.74-3.99 (m, 2.5H), 3.37-3.60(m, 1H), 3.06-3.28 (m, 2H), 2.92-3.06 (m, 1H), 2.53-2.83 (m, 3H), 2.12(dt, J=10.0, 6.5 Hz, 1H), 1.43-1.55 (m, 1H), 0.98-1.15 (m, 4H),0.72-0.97 (m, 5H)

LC-MS: m/z 497.3 (M+H)⁺

Compound 625 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.05-9.19 (m, 1H), 7.98 (ddd, J=6.1, 4.3, 2.1Hz, 1H), 7.63-7.68 (m, 1H), 7.55-7.61 (m, 1H), 7.41-7.47 (m, 1H),7.03-7.17 (m, 1H), 6.52 (d, J=17.6 Hz, 1H), 5.72-5.84 (m, 1H), 4.89 (br.s., 0.5H), 4.54 (d, J=12.5 Hz, 1H), 4.39 (d, J=13.8 Hz, 1H), 4.29 (d,J=19.8 Hz, 2H), 4.20 (br. s., 1H), 3.82-4.00 (m, 2.5H), 3.01-3.24 (m,2H), 2.46-2.76 (m, 3H), 1.06-1.19 (m, 2H), 0.75-0.94 (m, 3H)

LC-MS: m/z 469.2 (M+H)⁺

Compound 626 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.12 (S, 1h), 7.99 (br. s., 1H), 7.52-7.69 (m,2H), 7.36-7.50 (m, 1H), 7.00-7.19 (m, 1H), 6.53 (d, J=17.6 Hz, 1H), 5.78(d, J=10.8 Hz, 1H), 4.71 (br. s., 1.5H), 4.35-4.52 (m, 2H), 3.58-3.81(m, 3.5H), 3.37 (d, J=3.0 Hz, 4H), 3.18 (dd, J=13.6, 3.5 Hz, 2H),2.52-2.82 (m, 2H), 1.08 (dt, J=12.0, 5.7 Hz, 4H), 0.87 (d, J=6.8 Hz, 6H)

LC-MS: m/z 511.2 (M+H)⁺

Compound 599 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.14 (dd, J=4.1, 1.9 Hz, 1H), 7.98 (br. s., 1H),7.65 (s, 1H), 7.59 (s, 1H), 7.45 (dd, J=8.3, 4.3 Hz, 1H), 7.11 (d,J=10.8 Hz, 1H), 6.44-6.62 (m, 1H), 5.80 (d, J=10.8 Hz, 1H), 4.94 (br.S., 0.5H), 4.55 (br. s., 0.5H), 4.42 (br. s., 3H), 3.75 (d, J=6.3 Hz,3H), 3.39 (s, 4H), 3.15 (br. s., 2H), 2.63 (br. s., 2H), 1.10-1.22 (m,3H), 0.72-0.97 (m, 4H)

LC-MS: m/z 483.1 (M+H)⁺

Compound 596 (General Procedure 1, Step I)(R)-2′-cyclopropyl-6′-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-vinyl-2,3′-bipyridine-5′-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.67 (d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.50 (s,3H), 6.63-6.82 (m, 1H), 6.04 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.0 Hz,1H), 4.91 (br. s., 0.5H), 4.51 (br. s., 1H), 4.34 (br. s., 3H),3.65-3.83 (m, 2.5H), 3.33-3.44 (m, 4H), 3.29 (br. s., 1H), 2.71 (br. s.,1H), 2.62 (br. s., 2H), 1.33-1.43 (m, 3H), 1.15-1.25 (m, 4H)

LC-MS: m/z 431.2 (M+H)⁺

Compound 612 (General Procedure 1, Step I)(R)-5-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

1H NMR (CHLOROFORM-d) δ 7.48-7.56 (m, 1H), 6.31-6.57 (m, 2H), 5.97 (d,J=2.0 Hz, 1H), 5.65-5.88 (m, 1H), 4.01-4.90 (m, 8H), 3.02-3.81 (m, 3H),2.09-2.34 (m, 1H), 1.75 (br. s., 2H), 1.25-1.37 (m, 3H), 1.09-1.22 (m,2H), 0.95-1.09 (m, 4H), 0.67-0.94 (m, 2H)

LC-MS: m/z 432.2 (M+H)⁺

Compound 620 (General Procedure 1, Step I)(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-6′-vinyl-3,3′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.63 (d, J=2.0 Hz, 1H), 7.66-7.74 (m, 1H),7.58-7.65 (m, 1H), 7.40-7.50 (m, 1H), 6.87 (dd, J=17.6, 10.8 Hz, 1H),6.27 (dd, J=17.6, 1.0 Hz, 1H), 5.54 (dd, J=10.8, 1.0 Hz, 1H), 4.90 (br.s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.17-4.41 (m, 2.5H), 3.66-3.88 (m,2.5H), 3.54 (t, J=11.2 Hz, 0.5H), 3.37 (s, 3H), 3.28 (t, J=9.8 Hz, 1H),2.99-3.20 (m, 1.5H), 2.52-2.81 (m, 2H), 1.94-2.06 (m, 1H), 1.33-1.41 (m,1.5H), 1.24-1.29 (m, 1.5H), 1.14-1.23 (m, 2H), 0.91-1.04 (m, 2H)

LC-MS: m/z 432.1 (M+H)⁺

Compound 619 (General Procedure 1, Step I)(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,3′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.54-8.72 (m, 1H), 7.45-7.58 (m, 2H), 7.18-7.34(m, 1H), 6.53-6.69 (m, 1H), 6.38-6.47 (m, 1H), 5.43 (d, J=10.8 Hz, 1H),4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.14-4.39 (m, 2.5H),3.68-3.88 (m, 2.5H), 3.54 (d, J=4.8 Hz, 0.5H), 3.37 (s, 3H), 3.23-3.33(m, 1H), 2.99-3.21 (m, 1.5H), 2.51-2.80 (m, 2H), 1.55-1.69 (m, 1H), 1.39(br. s., 1.5H), 1.29 (br. s., 1.5H), 1.04-1.19 (m, 2H), 0.79-1.00 (m,2H)

LC-MS: m/z 432.2 (M+H)⁺

Compound 630 (General Procedure 1, Step I)(R)-5-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

1H NMR (CHLOROFORM-d) δ 7.45 (s, 1H), 6.64 (td, J=16.1, 10.7 Hz, 1H),6.29-6.42 (m, 1H), 5.67-5.86 (m, 2H), 4.00-5.00 (m, 6H), 3.85-3.93 (m,1H), 3.79 (t, J=5.3 Hz, 1H), 3.00-3.63 (m, 3H), 2.39-2.52 (m, 2H),1.96-2.12 (m, 1H), 1.75 (br. s., 1H), 1.28-1.51 (m, 3H), 1.08-1.17 (m,2H), 0.94-1.08 (m, 4H), 0.76-0.86 (m, 2H)

LC-MS: m/z 446.0 (M+H)⁺

Compound 557 (General Procedure 1, Step I)(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-methyl-1,8-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 0.39-0.53 (m, 1H) 0.56 (d, J=4.52 Hz, 3H)0.79-0.94 (m, 4H) 0.94-1.14 (m, 3H) 1.22 (br. s., 2H) 1.27 (br. s., 2H)1.33 (br. s., 2H) 3.01 (s, 3H) 4.53 (d, J=12.55 Hz, 2.5H) 7.46 (s, 1H)7.58 (br. s., 1H) 7.67 (s, 1H) 8.14 (br. s., 1H) 9.22 (br. s., 1H)

LC-MS: m/z 479.3 (M+H)⁺

Compound 552 (General Procedure 2, Step M) (R)-tert-butyl5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)pyridin-3-yl)-1H-indazole-1-carboxylate

70 mg of(R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(1H-indazol-5-yl)nicotinonitrile(NB247-78) (0.18 mmol), 83 mg of HATU (0.22 mmol), 37 mg of TEA in 10 mLof DCM was added 23 mg of 3,3,3-trifluoropropanoic acid (0.18 mmol),then the mixture was stirred at room temperature for 2 hours,concentrated, purified by Prep-TLC(Petroleum ether:Ethyl acetate=1:1) togive 31.5 mg of title compound. ¹H NMR (CHLOROFORM-d) 7.98 (br. s., 1H),7.77 (s, 1H), 7.42-7.62 (m, 2H), 7.15 (d, J=7.0 Hz, 1H), 4.56 (d, J=13.1Hz, 2H), 4.13 (br. s., 0.5H), 3.84 (br. s., 1.5H), 3.35 (d, J=10.0 Hz,2H), 3.23 (br. s., 2H), 3.12 (br. s., 1H), 1.94 (s, 1H), 1.15-1.32 (m,5H), 0.94 (dd, J=7.8, 3.3 Hz, 2H), 0.52 (d, J=5.3 Hz, 2H)

LC-MS: m/z 495.2 (M+H)⁺

Compound 537 (General Procedure 2, Step M)(R)-5-(benzo[d]thiazol-6-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.07 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.99 (d,J=1.5 Hz, 1H), 7.71 (s, 1H), 7.57 (dd, J=8.4, 1.6 Hz, 1H), 4.53 (d,J=13.3 Hz, 1H), 4.42 (d, J=12.8 Hz, 1H), 3.98-4.21 (m, 0.5H), 3.67-3.95(m, 1.5H), 3.26-3.38 (m, 2H), 3.15-3.26 (m, 2H), 3.09 (t, J=11.3 Hz,1H), 2.04-2.12 (m, 1H), 1.42 (d, J=14.3 Hz, 1H), 1.17-1.24 (m, 2H),0.95-1.03 (m, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.45-0.53 (m,2H)

LC-MS: m/z 512.1 (M+H)⁺

Compound 536 (General Procedure 2, Step M)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.45-8.58 (m, 1H), 7.59-7.69 (m, 2H), 7.47-7.59(m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 4.53 (d, J=13.1Hz, 1H), 4.43 (d, J=12.0 Hz, 1H), 4.12 (br. s., 0.5H), 3.78 (br. s.,1H), 3.67 (s, 3H), 3.33 (q, J=9.8 Hz, 2H), 3.16-3.26 (m, 1H), 3.03-3.16(m, 0.5H), 1.92 (br. s., 1H), 1.69-1.80 (m, 1H), 1.20-1.28 (m, 2H),1.07-1.19 (m, 2H), 0.81-0.95 (m, 2H), 0.67 (br. s., 1H), 0.57 (br. s.,1H), 0.43-0.54 (m, 2H)

LC-MS: m/z 536.2 (M+H)⁺

Compound 580 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

1H NMR (CHLOROFORM-d) d: 9.56 (s, 1H), 8.59 (d, J=5.8 Hz, 1H), 7.74 (s,1H), 7.64-7.70 (m, 1H), 7.44-7.52 (m, 1H), 7.11 (dd, J=17.7, 10.9 Hz,1H), 6.44 (dd, J=17.7, 1.6 Hz, 1H), 5.83 (d, J=11.0 Hz, 1H), 4.95 (br.s., 0.5H), 4.58 (d, J=11.3 Hz, 0.5H), 4.42 (d, J=11.3 Hz, 1.5H), 4.31(br. s., 1H), 3.86 (d, J=13.1 Hz, 0.5H), 3.72-3.81 (m, 2H), 3.55-3.68(m, 0.5H), 3.4 (s, 3H) 3.34-3.39 (m, 0.5H), 3.04-3.30 (m, 2H), 2.53-2.83(m, 2H), 1.47-1.55 (m, 1H), 1.37-1.46 (m, 1.5H), 1.29-1.37 (m, 1.5H),1.20 (t, J=4.9 Hz, 2H), 0.84-0.96 (m, 2H)

LC-MS: m/z 483.2 (M+H)⁺

Compound 609 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.50-9.65 (m, 1H), 8.60 (d, J=6.0 Hz, 1H),7.74-7.82 (m, 1H), 7.62-7.72 (m, 1H), 7.48-7.57 (m, 1H), 7.11 (dd,J=17.7, 10.9 Hz, 1H), 6.45 (dd, J=17.6, 1.8 Hz, 1H), 5.85 (d, J=11.0 Hz,1H), 4.93 (br. s., 0.5H), 4.50-4.64 (m, 0.5H), 4.40-4.49 (m, 1H),4.31-4.40 (m, 1H), 4.22 (br. s., 0.5H), 3.91-4.01 (m, 2H), 3.78 (d,J=11.3 Hz, 0.5H), 3.61 (d, J=11.8 Hz, 0.5H), 3.39 (d, J=13.6 Hz, 1H),3.10-3.31 (m, 1.5H), 2.65-2.80 (m, 1H), 2.52-2.65 (m, 1H), 1.43-1.54 (m,3H), 1.35 (t, J=5.6 Hz, 2H), 1.21 (dd, J=6.9, 3.6 Hz, 2H), 0.87-0.98 (m,2H)

LC-MS: m/z 469.2 (M+H)⁺

Compound 611 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) d: 9.57 (s, 1H), 8.60 (dd, J=5.6, 3.1 Hz, 1H),7.75 (d, J=12.0 Hz, 1H), 7.66 (dd, J=4.8, 3.3 Hz, 1H), 7.45-7.55 (m,1H), 7.04-7.17 (m, 1H), 6.44 (d, J=17.6 Hz, 1H), 5.84 (d, J=10.8 Hz,1H), 4.61-4.81 (m, 1.5H), 4.42-4.56 (m, 1.5H), 3.92 (d, J=13.6 Hz,0.5H), 3.70-3.83 (m, 2H), 3.44-3.56 (m, 0.5H), 3.37-3.43 (m, 3H),3.08-3.31 (m, 2H), 2.90-3.05 (m, 0.5H), 2.55-2.85 (m, 2H), 1.49 (dd,J=7.4, 4.4 Hz, 1H), 1.14-1.32 (m, 2H), 1.11 (ddd, J=15.2, 6.5, 4.1 Hz,4H), 0.83-0.98 (m, 5H)

LC-MS: m/z 511.3 (M+H)⁺

Compound 542(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinylquinolin-4-yl)nicotinonitrile

Step 1

To 10 mg PdCl2(dppf).CH₂Cl₂ in a reaction tube under nitrogen were added5 mL dioxane, 3 mL water, 150 mg (0.98 mmol) CsF, 75 mg (0.43 mmol)quinolin-4-ylboronic acid and 150 mg (0.36 mmol)(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile.The reaction solution was heated to 100° C. for half hour undermicrowave irradiation. The reaction was extracted with ethyl acetate,washed several times with water and purified by TLC preparation(petroleum ether:ethyl acetate=1:1) to give desired compound 50 mg (32%,yield). LC-MS: m/z 438.22 (M+H)⁺

Step 2

To a stirred solution of(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(quinolin-4-yl)nicotinonitrile(50 mg, 0.108 mmol) in 10 mL of anhydrous CH₂Cl₂ was added3-chlorobenzoperoxoic acid (37 mg, 0.216 mmol) portionwise over 1 min.The resulting mixture was stirred at room temperature for 3 hours. Thensaturated aqueous Na2SO3 (10 mL) was added to the reaction. The reactionwas extracted with ethyl acetate to give desired compound(R)-4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinoline1-oxide 48 mg (93%). LC-MS: m/z 453.22 (M+H)⁺

Step 3

To a solution of(R)-4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinoline1-oxide (35 mg, 0.07 mmol) in 20 mL of CHCl3 was added POCl₃ (32 mg,0.209) dropwise at room temperature. The reaction mixture was thenheated at reflux for 3 hours. After LC-MS showed completion of reaction,the mixture was cooled to room temperature and poured into water andextracted with methylene chloride. The combined organic layer was driedover anhy. Na₂SO₄ and concentrated in vacuo to give the title compoundas a brown solid 30 mg (83.3%). LC-MS: m/z 472.18 (M+H)⁺

Step 4 is Similar to Compound 390 Step 2: Compound 542

¹H NMR (CHLOROFORM-d) d: 8.21 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.5 Hz, 1H),7.68 (d, J=1.0 Hz, 1H), 7.48-7.66 (m, 3H), 7.13 (dd, J=17.4, 10.9 Hz,1H), 6.35 (d, J=17.6 Hz, 1H), 5.76 (d, J=11.0 Hz, 1H), 4.61 (d, J=12.5Hz, 1.5H), 4.49 (d, J=12.3 Hz, 1.5H), 4.12 (br. s., 1H), 3.67-3.82 (m,1H), 3.34 (br. s., 1.5H), 3.19 (br. s., 1.5H), 1.58 (ddd, J=12.0, 7.8,4.5 Hz, 1H), 1.14-1.35 (m, 4H), 1.00-1.13 (m, 2H), 0.76-0.93 (m, 4H),0.71 (br. s., 1H), 0.38-0.63 (m, 3H)

LC-MS: m/z 490.6 (M+H)⁺

Compound 543(R)-5-(2-chloroquinolin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (CHLOROFORM-d) d: 8.12 (d, J=8.3 Hz, 1H), 7.76-7.84 (m, 1H),7.61-7.68 (m, 2H), 7.53-7.61 (m, 1H), 7.38 (d, J=1:8 Hz, 1H), 4.63 (d,J=12.5 Hz, 1H), 4.51 (d, J=12.5 Hz, 1H), 3.97-4.20 (m, 1H), 3.82 (br.s., 1H), 3.59-3.78 (m, 1H), 3.34 (br. s., 1H), 3.20 (br. s., 1H), 1.74(br. s., 2H), 1.50-1.59 (m, 1H), 1.14-1.26 (m, 2H), 0.97-1.14 (m, 2H),0.79-0.97 (m, 4H), 0.70 (br. s., 1H), 0.42-0.63 (m, 3H)

LC-MS: m/z 499.0 (M+H)⁺

Compound 571(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylquinolin-4-yl)nicotinonitrile

The synthesis was similar to Compound 542.

1H NMR (CHLOROFORM-d) d: 8.18 (d, J=8.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H),7.69 (d, J=1.0 Hz, 1H), 7.46-7.64 (m, 3H), 7.11 (dd, J=17.7, 10.9 Hz,1H), 6.28-6.39 (m, 1H), 5.75 (d, J=11.0 Hz, 1H), 4.59 (d, J=13.1 Hz,1H), 4.47 (d, J=13.1 Hz, 1H), 4.13 (d, J=8.3 Hz, 0.5H), 3.94 (br. s.,2H), 3.82 (br. s., 1H), 3.76 (br. s., 1H), 3.43 (br. s., 1H), 3.21-3.37(m, 1.5H), 3.15 (d, J=11.5 Hz, 1H), 2.55-2.70 (m, 2H), 1.67 (br. s.,1H), 1.59 (tt, J=8.1, 4.3 Hz, 1H), 1.10-1.24 (m, 2H), 0.80-0.94 (m, 2H),0.69 (br. s., 1H), 0.58 (br. s., 1H), 0.51 (br. s., 2H)

LC-MS: m/z 494.2 (M+H)⁺

Compound 574(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylquinolin-4-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (CHLOROFORM-d) δ 8.15 (d, J=8.5 Hz, 1H), 7.71-7.78 (m, 1H), 7.67(d, J=1.0 Hz, 1H), 7.56-7.64 (m, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.46-7.53(m, 1H), 7.02-7.14 (m, 1H), 6.32 (dd, J=17.6, 1.3 Hz, 1H), 5.73 (d,J=11.3 Hz, 1H), 4.71-4.74 (m, 0.5H), 4.53-4.66 (m, 1H), 4.45 (d, J=13.1Hz, 1H), 4.06-4.24 (m, 0.5H), 3.91 (d, J=11.5 Hz, 0.5H), 3.68-3.84 (m,3H), 3.39 (s, 3H), 3.26 (br. s., 1.5H), 3.07-3.21 (m, 1H), 2.61-2.85 (m,2H), 1.53-1.64 (m, 1H), 1.32-1.44 (m, 1H), 1.11-1.24 (m, 2H), 0.80-0.94(m, 2H), 0.48-0.78 (m, 1H)

LC-MS: m/z 508.1 (M+H)⁺

Compound 591(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylypiperazin-1-yl)-5-(2-vinylquinolin-4-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (CHLOROFORM-d) δ 8.18 (d, J=8.3 Hz, 1H), 7.76 (ddd, J=8.3, 6.8,1.4 Hz, 1H), 7.68 (s, 1H), 7.57-7.63 (m, 1H), 7.48-7.57 (m, 2H), 7.10(dd, J=17.7, 10.9 Hz, 1H), 6.34 (dd, J=17.6, 1.8 Hz, 1H), 5.74 (d,J=11.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.48-4.68 (m, 0.5H), 4.26-4.45 (m,2H), 3.87-3.98 (m, 2H), 3.74-3.87 (m, 0.5H), 3.61 (t, J=12.3 Hz, 0.5H),3.31-3.48 (m, 2H), 3.05-3.29 (m, 1H), 2.49-2.79 (m, 2H), 1.53-1.63 (m,1H), 1.46 (dd, J=6.5, 2.5 Hz, 1.5H), 1.32-1.40 (m, 1.5H), 1.15-1.23 (m,2H), 0.80-0.93 (m, 2H)

LC-MS: m/z 468.2 (M+H)⁺

Compound 592(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinolin-4-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (CHLOROFORM-d) δ 8.19 (d, J=8.3 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H),7.65-7.68 (m, 1H), 7.58-7.64 (m, 1H), 7.48-7.57 (m, 2H), 7.11 (dd,J=17.7, 10.9 Hz, 1H), 6.34 (d, J=17.8 Hz, 1H), 5.75 (d, J=10.8 Hz, 1H),4.95 (br. s., 0.5H), 4.50-4.70 (m, 0.5H), 4.24-4.47 (m, 2.5H), 3.71-3.89(m, 2.5H), 3.59 (d, J=9.8 Hz, 0.5H), 3.31-3.45 (m, 4H), 3.07-3.28 (m,1.5H), 2.67-2.85 (m, 1H), 2.54-2.67 (m, 1H), 1.52-1.62 (m, 1H),1.33-1.49 (m, 3H), 1.11-1.21 (m, 2H), 0.78-0.93 (m, 2H)

LC-MS: m/z 482.2 (M+H)⁺

Compound 553 (General Procedure 1, Step I)(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-methyl-1,7-naphthyridin-4-yl)nicotinonitrile

1H NMR (CHLOROFORM-d) d: 9.53 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 7.65 (s,1H), 7.42-7.50 (m, 2H), 4.63 (d, J=9.3 Hz, 1H), 4.51 (d, J=11.0 Hz,2.5H), 3.08-3.48 (m, 4.5H), 2.87 (s, 3H), 1.59-1.68 (m, 1H), 1.46-1.53(m, 1H), 1.22 (d, J=3.0 Hz, 1H), 1.05-1.11 (m, 2H), 0.92-0.98 (m, 2H),0.87-0.92 (m, 2H), 0.84 (dd, J=7.9, 2.6 Hz, 2H), 0.70 (br. s., 1H),0.42-0.63 (m, 3H)

LC-MS: m/z 479.6 (M+H)⁺

Compound 551(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(2-vinylquinolin-5-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J=8.2 Hz, 1H), 7.91 (dd,J=12.5, 8.8 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.64-7.71 (m, 1H),7.57-7.64 (m, 1H), 7.46 (dd, J=6.9, 2.3 Hz, 1H), 6.97-7.17 (m, 1H), 6.34(d, J=17.8 Hz, 1H), 5.75 (d, J=10.7 Hz, 1H), 4.56 (dd, J=13.0, 1.7 Hz,1H), 4.45 (d, J=11.8 Hz, 1H), 4.15 (m, 0.5H), 3.87 (m, 1.5H), 3.26-3.44(m, 2.5H), 3.01-3.20 (m, 2.5H), 1.42-1.52 (m, 1H), 1.07-1.21 (m, 2H),0.79-0.92 (m, 3H), 0.66-0.76 (m, 2H), 0.46-0.56 (m, 2H)

LC-MS: m/z 532.2 (M+H)⁺

Compound 570(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylquinolin-5-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.11-8.17 (m, 1H), 7.85-7.95 (m, 1H),7.78 (t, J=7.3 Hz, 1H), 7.64-7.68 (m, 1H), 7.60 (dd, J=8.8, 1.5 Hz, 1H),7.42-7.47 (m, 1H), 7.00-7.13 (m, 1H), 6.32 (d, J=17.6 Hz, 1H), 5.72 (d,J=11.0 Hz, 1H), 4.72 (m, 0.5H), 4.54 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.8Hz, 1H), 4.14 (d, J=7.8 Hz, 0.5H), 3.91 (d, J=11.8 Hz, 0.5H), 3.75 (t,J=5.6 Hz, 2.5H), 3.40 (s, 3H), 3.23 (d, J=8.0 Hz, 1H), 3.01-3.17 (m,1H), 2.70-2.81 (m, 1H), 2.67 (m, 1H), 2.03 (d, J=5.5 Hz, 1H), 1.56 (td,J=7.8, 4.0 Hz, 1H), 1.11-1.20 (m, 3H), 0.78-0.86 (m, 2H), 0.58-0.66 (m,2H), 0.42-0.52 (m, 2H)

LC-MS: m/z 508.2 (M+H)⁺

Compound 569(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylquinolin-5-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (400 MHz, CHLOROFORM-d) δ8.10-8.19 (m, 1H), 7.90 (dd, J=12.3, 8.8Hz, 1H), 7.74-7.82 (m, 1H), 7.67 (s, 1H), 7.58-7.63 (m, 1H), 7.45 (ddd,J=7.0, 3.0, 1.0 Hz, 1H), 7.07 (dd, J=17.6, 10.9 Hz, 1H), 6.33 (d, J=17.5Hz, 1H), 5.73 (d, J=11.0 Hz, 1H), 4.72 (d, J=9.5 Hz, 0.5H), 4.55 (d,J=13.0 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.12 (d, J=7.2 Hz, 0.5H),3.87-3.99 (m, 2H), 3.73-3.84 (m, 1H), 3.46 (m, 1H), 3.26 (m, 1.5H), 3.13(d, J=10.5 Hz, 1H), 2.59-2.68 (m, 1.5H), 2.03 (d, J=6.0 Hz, 1H),1.54-1.59 (m, 1H), 1.11-1.19 (m, 3H), 0.86-0.94 (m, 2H), 0.80-0.86 (m,2H), 0.51-0.57 (m, 2H)

LC-MS: m/z 493.3 (M+H)⁺

Compound 608(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinolin-5-yl)nicotinonitrile

The synthesis was similar to Compound 542.

1H NMR (400 MHz, CHLOROFORM-d) δ8.16-8.24 (m, 1H), 7.90-7.97 (m, 1H),7.76-7.83 (m, 1H), 7.59-7.66 (m, 2H), 7.46 (d, J=7.0 Hz, 1H), 7.12 (dd,J=17.6, 10.9 Hz, 1H), 6.35 (d, J=17.5 Hz, 1H), 5.76 (d, J=11.0 Hz, 1H),4.95 (m, 0.5H), 4.58 (d, J=12.5 Hz, 0.5H), 4.19-4.44 (m, 2.5H),3.67-3.91 (m, 1.5H), 3.40 (s, 3H), 3.15-3.26 (m, 1.5H), 2.67-2.82 (m,1.5H), 2.03 (d, J=5.7 Hz, 1H), 1.55 (td, J=8.0, 4.1 Hz, 1H), 1.31-1.37(m, 3H), 1.11-1.18 (m, 2H) 0.77-0.86 (m, 2H)

LC-MS: m/z 482.2 (M+H)⁺

Compound 633 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinolin-5-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=8.2 Hz, 1H), 7.87-7.99 (m,1H), 7.75-7.85 (m, 1H), 7.58-7.69 (m, 2H), 7.41-7.50 (m, 1H), 7.12 (dd,J=17.0, 11.0 Hz, 1H), 6.35 (d, J=17.5 Hz, 1H), 5.76 (d, J=11.0 Hz, 1H),4.93 (m, 0.5H), 4.51-4.61 (m, 0.5H), 4.37 (d, J=12.8 Hz, 1H), 4.21-4.29(m, 1H), 3.88-3.99 (m, 2H), 3.77 (d, J=12.0 Hz, 0.5H), 3.60 (t, J=12.3Hz, 0.5H), 3.27-3.44 (m, 2H), 3.02-3.26 (m, 1H), 2.49-2.79 (m, 2H),1.96-2.07 (m, 1H), 1.51-1.60 (m, 1H), 1.27 (s, 3H), 1.08-1.17 (m, 2H),0.77-0.87 (m, 2H)

LC-MS: m/z 468.2 (M+H)⁺

Compound 637(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinazolin-4-yl)nicotinonitrile

The synthesis was similar to Compound 542.

¹H NMR (CHLOROFORM-d) δ 8.07 (d, J=8.3 Hz, 1H), 7.85-7.96 (m, 2H), 7.81(d, J=8.0 Hz, 1H), 7.57 (td, J=7.7, 1.0 Hz, 1H), 7.08 (dd, J=17.3, 10.5Hz, 1H), 6.81 (dd, J=17.3, 1.8 Hz, 1H), 5.79-5.94 (m, 1H), 4.82-4.98 (m,0.5H), 4.54 (d, J=12 Hz, 0.5H), 4.29-4.48 (m, 2H), 3.93 (br. s., 2H),3.69-3.82 (m, 0.5H), 3.52-3.66 (m, 0.5H), 3.43-3.52 (m, 1H), 3.31-3.43(m, 1H), 3.01-3.30 (m, 1.5H), 2.47-2.77 (m, 2H), 1.64-1.79 (m, 1H), 1.42(d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.11-1.24 (m, 2H), 0.90(d, J=5.8 Hz, 2H)

LC-MS: m/z 469.2 (M+H)⁺

Compound 334 (General Procedure 1, Step H)(R)-6-cyclopropyl-5-(2-ethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (METHANOL-d) δ 7.59 (s, 1H), 7.33-7.36 (d, J=4.4 Hz, 2H),7.24-7.27 (m, 1H), 7.12-7.13 (d, J=7.6 Hz, 1H), 4.40-4.46 (m, 1H),4.14-4.23 (m, 2H), 3.92-3.96 (d, J=14.4 Hz, 0.5H), 3.34 (s, 3H),3.14-3.19 (m, 2H), 3.34 (s, 4H), 2.99-3.14 (m, 0.5H), 2.60-2.81 (m, 2H),2.46-2.50 (m, 2H), 1.64-1.69 (m, 1H), 1.37-1.41 (q, J=7.2 Hz, 1.3H),1.26-1.30 (t, J=6.4 Hz, 1.7H), 1.02-1.11 (m, 5H), 0.82-0.91 (m, 2H);LC-MS: m/z 433.6 (M+H)

Compound 357 (General Procedure 1, Step H)(R)-6-cyclopropyl-5-(2,6-dimethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (METHANOL-d) δ 7.48 (s, 1H), 7.11-7.18 (m, 3H), 4.79 (s, 1H),4.39-4.45 (m, 1H), 4.21-4.24 (d, J=12.8 Hz, 1.5H), 4.13-4.17 (d, J=13.2Hz, 0.5H), 3.91-3.95 (d, J=13.6 Hz, 0.5H), 3.66-3.69 (t, J=5.2 Hz, 2H),3.55-3.61 (t, J=7.2 Hz, 0.5H), 3.34 (s, 4H), 3.10-3.21 (m, 1H),2.96-3.01 (m, 0.5H), 2.69-2.80 (m, 1H), 2.60-2.65 (m, 1H), 2.01-2.02 (d,J=2.8 Hz, 6H), 1.51-1.57 (m, 1H), 1.38-1.39 (d, J=6.4 Hz, 1.3H),1.26-1.28 (d, J=6.8 Hz, 1.7H), 1.08-1.11 (m, 1H), 0.75-0.91 (m, 2H)LC-MS: m/z 433.2 (M+H)

Compound 344 (General Procedure 1, Step H)(R)-6-cyclopropyl-5-(2-hydroxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) δ 7.63 (s, 1H), 7.58-7.60 (d, J=7.6 Hz, 1H),7.40-7.44 (t, J=7.6 Hz, 1H), 7.33-7.36 (t, J=7.6 Hz, 1H), 7.16-7.18 (d,J=7.6 Hz, 1H), 4.78 (s, 1H), 4.36-4.49 (m, 3H), 4.13-4.24 (m, 2H),3.91-3.95 (d, J=13.2 Hz, 0.5H), 3.66-6.69 (m, 2H), 3.54-3.61 (m, 0.5H),3.33-3.34 (m, 4H), 3.25-3.28 (m, 0.5H), 3.13-3.15 (m, 1H), 2.96-3.02 (m,0.5H), 2.69-2.81 (m, 1H), 2.60-2.65 (m, 1H), 1.62-1.68 (m, 1H),1.37-1.39 (m, 1.5H), 1.25-1.28 (m, 1.5H), 1.11-1.12 (m, 2H), 0.83-0.92(m, 2H); LC-MS: m/z 435.2 (M+H)

Compound 328 (General Procedure 1, Step H)(R)-2-cyclopropyl-2′-methoxy-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-[3,3′]bipyridinyl-5-carbonitrile

¹H NMR (METHANOL-d) δ 8.17-8.18 (dd, J=4.8 Hz, 1H), 7.65 (s, 1H),7.61-7.63 (dd, J=7.2 Hz, 1H), 7.04-7.07 (dd, J=7.2 Hz, 1H), 4.76-4.78(m, 0.5H), 4.38-4.44 (m, 1H), 4.13-4.25 (m, 2H), 3.90 (s, 3H), 3.66-3.69(t, J=5.6 Hz, 2H), 3.54-6.60 (m, 0.5H), 3.33 (s, 3H), 3.15-3.19 (m,0.5H), 3.12-3.13 (m, 1H), 2.97-3.03 (m, 0.5H), 2.69-2.80 (m, 1H),2.59-2.65 (m, 1H), 1.67-1.73 (m, 1H), 1.37-1.38 (d, J=6.4 Hz, 1H),1.25-1.27 (d, J=6.8 Hz, 2H), 1.10-1.11 (m, 2H), 0.85-0.92 (m, 2H)

LC-MS: m/z 436.2 (M+H)

Compound 338 (General Procedure 1, Step H)(R)-6-cyclopropyl-5-[2-(2-methoxy-ethyl)-phenyl]-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) δ 7.63 (s, 1H), 7.51-7.53 (d, J=6.4 Hz, 1H),7.39-7.42 (m, 2H), 7.22-7.23 (dd, J=6.8 Hz, 1H), 4.15-4.45 (m, 4H),3.93-3.96 (m, 0.5H), 3.66-3.69 (m, 2H), 3.34 (s, 4H), 3.16-3.17 (d,J=4.0 Hz, 3H), 3.13-3.14 (m, 0.5H), 3.00-3.04 (m, 0.5H), 2.70-2.81 (m,1H), 2.61-2.64 (m, 1H), 1.63-1.67 (m, 1H), 1.38-1.40 (m, 1H), 1.26-1.29(m, 2H), 1.12-1.25 (m, 2H), 0.83-0.94 (m, 2H) LC-MS: m/z 449.2 (M+H)

Compound 360 (General Procedure 1, Step H)(R)-5-(2-chloro-quinolin-3-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) δ 8.38 (S, 1H), 8.00-8.02 (m, 2H), 7.85 (t, J=7.2Hz, 2H), 7.81 (S, 1H), 7.68 (t, J=8.0 Hz, 1H), 4.8 (m, 1H), 4.4-4.5 (m,1H), 4.2-4.4 (m, 1H), 3.95 (d, J=14.0 Hz, 0.5H), 3.67 (t, J=18.0 Hz,2h), 3.54-3.60 (m, 0.5H), 3.32-3.45 (m, 4.5H), 3.22-3.25 (m, 1H),3.09-3.22 (m, 0.5H), 2.71-2.79 (m, 1H), 2.60-2.65 (m, 1H), 1.63-1.69 (m,1H), 1.39-1.41 (m, 1H), 1.30 (t, J=6.8 Hz, 2H), 1.18-1.24 (m, 1H),1.12-1.17 (m, 1H), 0.95-1.15 (m, 1H), 0.85-0.95 (m, 1H).

LC-MS: m/z 490.1 (M+H)+.

Compound 371 (General Procedure 1, Step H)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(2-methyl-2H-pyrazol-3-yl)-nicotinonitrile

1H NMR (METHANOL-d) δ 7.77 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 6.36 (d,J=2.0 Hz, 1H), 4.78 (m, 0.5H), 4.21-4.44 (m, 3H), 3.94 (d, J=12.6 Hz,0.5H), 3.66-3.69 (m, 4.5H), 3.54-3.62 (m, 0.5H), 3.33 (m, 3.5H),2.70-2.82 (m, 1H), 2.59-2.65 (m, 1H), 1.68-1.74 (m, 1H), 1.36 (d, J=6.8Hz, 1H), 1.27 (d, J=11.2 Hz, 2H), 1.14-1.24 (m, 2H), 0.97-1.02 (m, 2H).LC-MS: m/z 409.2 (M+H)⁺.

Compound 345 (General Procedure 1, Step H)(R)-6-cyclopropyl-5-(3,5-dimethyl-isoxazol-4-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) δ 7.70 (s, 1H), 4.77-4.80 (m, 0.5H), 4.42 (d, J=13.2Hz, 1H), 4.17-4.28 (m, 2H), 3.94 (d, J=13.2 Hz, 0.5H), 3.68 (t, J=5.2Hz, 2H), 3.51-3.62 (m, 1H), 3.31-3.33 (m, 3H), 3.14-3.24 (m, 1H),3.01-3.08 (m, 0.5H), 2.71-2.80 (m, 1H), 2.59-2.70 (m, 1H), 2.30 (s, 3H),2.14 (s, 3H), 1.75-1.82 (m, 1H), 1.38 (d, J=6.8 Hz, 1H), 1.25 (d, J=11.2Hz, 2H), 1.15-1.20 (m, 2H), 0.98-1.02 (m, 2H). LC-MS: m/z 424.2 (M+H)+.

Compound 394 (General Procedure 1, Step H)(R)-6-cyclopropyl-5-(1H-indol-2-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.27 (s, 1H), 7.79 (s, 1H0, 7.64 (d, J=8.0 Hz,1H), 7.23 (t, J=8.0 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.65 (t, J=1.2 Hz,1H), 4.89 (s, 0.5H), 4.52 (d, J=13.2 Hz, 0.5H), 4.23-4.35 (m, 2.5H),3.72-3.77 (m, 2.5H), 3.54-3.60 (m, 0.5H), 3.37 (s, 3H), 3.26-3.32 (m,1H), 3.04-3.17 (m, 1H), 2.55-2.72 (m, 2H), 2.36-2.43 (m, 1H), 1.37 (d,J=5.6 Hz, 1H), 1.26 (d, J=6.8 Hz, 2H), 1.18-1.20 (m, 2H), 1.03-1.04 (m,2H). LC-MS: m/z 444.2 (M+H)⁺.

Compound 361 (General Procedure 1, Step I)(R)-5-(1H-benzoimidazol-5-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (METHANOL-d) 8.226 (s, 1H), 7.764 (s, 1H), 7.697-7.614 (m, 2H),7.333-7.313 (d, J=8 Hz, 2H), 4.775-4.856 (m, 0.5H), 4.459-4.389 (m, 1H),4.268-4.147 (m, 2H), 3.968-3.929 (m, 0.5H), 3.688-3.567 (m, 3H), 3.342(s, 3H), 3.193-3.022 (m, 2H), 2.814-2.626 (m, 2H), 2.125-2.076 (m, 1H),1.402-1.274 (m, 3H), 1.175 (s, 2H), 1.54-0.928 (m, 2H). LC-MS: m/z 445.1(M+H)⁺.

Compound 352 (General Procedure 1, Step I)(R)-5-benzothiazol-5-yl-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) 9.301 (s, 1H), 8.163-8.142 (d, J=8.4 Hz, 1H),8.102-8.099 (d, J=1.2, 1H), 7.807 (s, 1H), 7.559-7.535 (dd, J1=9.6 Hz,J2=1.6 Hz, 1H), 4.792 (m, 0.5H), 4.453-4.418 (m, 1H), 4.282-4.170 (m,2H), 3.959-3.926 (m, 0.5H), 3.682-3.667 (m, 2H), 3.616-3.561 (m, 0.5H),3.338 (s, 3H), 3.212-3.004 (m, 2H), 2.806-2.594 (m, 2H), 2.085-2.022 (m,1H), 1.392-1.262 (m, 3H), 1.211-1.176 (m, 2H), 1.000-0.900 (m, 2H).LC-MS: m/z 462.1 (M+H)+.

Compound 364 (General Procedure 1, Step I)(R)-5-benzothiazol-6-yl-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) 9.292 (s, 1H), 8.131 (s, 2H), 7.806 (s, 1H),7.624-7.606 (d, J=7.2 Hz, 1H), 4.775-4.856 (m, 0.5H), 4.412-4.172 (m,3H), 3.960-3.931 (m, 0.5H), 3.555-3.688 (m, 3H), 3.345 (s, 3H),3.188-3.038 (m, 2H), 2.762-2.640 (m, 2H), 2.047-2.035 (m, 1H),1.379-1.266 (m, 3H), 1.192 (s, 2H), 0.965 (s, 2H). LC-MS: m/z 462.0(M+H)+.

Compound 417 (General Procedure 1, Step I)(R)-5-(2-amino-benzothiazol-6-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (CHLOROFORM-d) 7.844 (s, 1H), 7.719-7.715 (d, J=1.6 Hz, 1H),7.547 (s, 2H), 7.402-7.381 (d, J=8.4 Hz, 1H), 7.266-7.242 (d, J=9.6,1H), 4.631-4.664 (m, 0.5H), 4.297-4.017 (m, 3H), 3.869-3.838 (m, 0.5H),3.564-3.453 (m, 3H), 3.349-3.228 (m, 3H), 3.109-2.929 (m, 2H),2.669-2.500 (m, 2H), 2.081-2.058 (m, 1H), 1.236 (s, 1H), 1.135-1.079 (m,4H), 0.964-0.936 (m, 2H). LC-MS: m/z 477.1 (M+H)+.

Compound 370 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-tetrazolo[1,5-a]pyridin-6-yl-nicotinonitrile

1H NMR (METHANOL-d) 9.213-9.215 (d, J=0.8 Hz, 1H), 8.131-8.154 (d, J=9.2Hz, 1H), 7.917-7.947 (m, 2H), 4.784 (s, 0.5H), 4.220-4.782 (m, 3H),3.973-3.939 (d, J=13.6 Hz, 0.5H), 3.680 (s, 0.5H), 3.051-3.40 (m, 6H),2.595-2.821 (m, 2H), 1.973-2.033 (m, 1H), 1.231-1.369 (m, 5H),0.90-1.120 (s, 2H). LC-MS: m/z 447.1 (M+H)+.

Compound 367 (General Procedure 1, Step I)(R)-6-cyclopropyl-5-isoquinolin-8-yl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) 9.342-9.356 (d, J=5.6 Hz, 1H), 8.626-8.642 (d, J=6.4Hz, 1H), 8.530-8.546 (d, J=6.4 Hz 1H), 8.347-8.368 (d, J=8.4 Hz 1H),8.263-8.284 (d, J=8.4 Hz 1H), 7.976-7.994 (d, J=7.2 Hz, 1H), 7.912 (s,1H), 4.814 (s, 0.5H), 4.265-4.808 (m, 3H), 3.968-4.002 (m, 2.5H),3.151-3.441 (m, 5H), 2.622-2.804 (m, 2H), 1.182-1.496 (m, 5H),0.801-0.981 (m, 2H). LC-MS: m/z 456.1 (M+H)⁺.

Compound 373 (General Procedure 1, Step I)(R)-6-cyclopropyl-5-(1H-indol-7-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) 7.759 (s, 1H), 7.579-7.599 (d, J=8 Hz, 1H), 7.218(s, 1H), 7.080-7.099 (d, J=7.6 Hz 1H), 7.000-7.018 (d, J=7.2 Hz 1H),6.506-6.513 (d, J=7.2 Hz, 1H), 4.417-4.466 (dd, J=8 Hz, 1H), 4.191-4.261(m, 3H), 3.940-3.976 (d, J=1.44 Hz, 0.5H), 3.603-3.642 (m, 3H),2.617-3.346 (m, 7H), 1.717-1.828 (m, 1H), 1.155-1.421 (m, 5H),0.832-0.851 (dd, J=4.4 HZ, 2H). LC-MS: m/z 444.2 (M+H)+.

Compound 353 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-quinolin-6-yl-nicotinonitrile

¹H NMR (METHANOL-d) 9.170-9.183 (d, J=5.2 Hz, 1H), 9.076-9.097 (d, J=8.4Hz, 1H), 8.304-8.333 (t, 2H), 8.194-8.216 (d, J=8.8 Hz 1H), 8017-8.050(m, 1H), 7.918 (s, 1H), 4.787 (s, 0.5H), 4.214-4.447 (m, 3H),3.974-4.214 (d, J=96 Hz, 0.5H), 3.336-3.397 (m, 3H), 3.076-3.3.250 (m,5H), 2.599-2.811 (m, 2H), 2.023-2.043 (m, 1H), 1.363-1.379 (d, J=6.4 Hz1H), 1.244-1.263 (d, J=7.6 Hz 4H), 0.99-1.026 (m, 2H). LC-MS: m/z 456.1(M+H)+.

Compound 374 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-nicotinonitrile

¹H NMR (METHANOL-d) 8.313 (s, 1H), 8.280 (s, 1H), 7.831 (s, 1H),7.563-7.572 (d, J=3.6 Hz 1H), 6.682-6.690 (d, J=3.2 Hz 1H), 4.795 (s,0.5H), 4.183-4.455 (m, 3H), 3.929-3.969 (m, 0.5H), 3.568-3.687 (m, 3H),3.179-3.342 (m, 4H), 3.046-3.078 (m, 1H), 2.609-2.810 (m, 2H), 2.020 (s,1H), 1.194-1.392 (m, 5H), 0.964-0.991 (m, 2H). LC-MS: m/z 445.2 (M+H)+.

Compound 395 (General Procedure 1, Step I)(R)-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-thiazol-2-yl)-carbamicacid tert-butyl ester

¹H NMR (CHLOROFORM-d) 8.282 (s, 1H), 7.884-7.889 (d, J=2 Hz, 1H),6.947-6.951 (d, J=1.6 Hz, 1H), 4.888 (s, 0.5H), 4.493-4.524 (d, J=12.4Hz, 0.5H), 4.205-4.371 (m, J=44.8 Hz, 2.5H), 3.719-3.790 (m, J=28.4 Hz,2.5H), 3.499-3.550 (m, J=20.4, 0.5H), 3.367-3.372 (d, J=2 Hz, 3H),3.218-3.246 (t, J=11.2 Hz, 1H), 3.006-3.118 (m, J=44.8 Hz, 1.5H),2.544-2.745 (m, J=80.4 Hz, 2H), 2.404-2.465 (m, J=24.4 Hz, 1H), 1.532(s, 9H), 1.243-1.355 (q, J=44.8 Hz, 3H), 1.153-1.158 (d, J=2 Hz, 2H),0.969-0.985 (t, J=6.4 Hz, 2H). LC-MS: m/z 527.2 (M+H)+.

Compound 418 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(2-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl)-nicotinonitrile

1H NMR (CHLOROFORM-d) 8.506-8.526 (d, J=8.0 Hz, 1H), 7.617-7.658 (t,J=16.4 Hz, 1H), 7.596 (s, 1H), 7.529-7.569 (t, J=16 Hz, 1H), 7.209-7.240(t, J=12.4 Hz, 1H), 7.036 (s, 1H), 4.916 (s, 0.5H), 4.534-4.642 (m,J=43.2 Hz, 3H), 4.208-4.351 (m, J=57.2 Hz, 3H), 3.836-3.869 (m, J=13.2Jz, 0.5H), 3.681-3.739 (t, J=23.2 Hz, 2H), 3.589 (s, 3H), 3.287-3.371(m, J=33.6 Hz, 1H), 3.155-3.192 (m, 1.5H), 2.594-2.773 (m, 2H),1.678-1.740 (m, J=24.8 Hz, 1H), 1.301-1.423 (d, J=48.8 Hz, 3H),1.089-1.143 (m, 2H), 0.809-0.909 (m, 2H). LC-MS: m/z 486.2 (M+H)+.

Compound 354 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(4-morpholin-4-yl-phenyl)-nicotinonitrile

1H NMR (CHLOROFORM-d) 7.665 (s, 1H), 7.348-7.327 (d, J=8.4 Hz, 2H),7.129-7.107 (d, J=8.8 Hz, 2H), 4.824-4.780 (m, 1H), 4.440-4.408 (m, 1H),4.220-4.109 (m, 2H), 3.884-3.860 (m, 4H), 3.693-3.520 (m, 3H), 3.361-3.4(s, 3H), 3.230-3.298 (m, 4.5H), 3.183-2.988 (m, 1.5H), 2.798-2.600 (m,2H), 2.115-2.076 (m, 1H), 1.382-1.253 (m, 3H), 1.162-1.128 (m, 2H),0.986-0.957 (m, 2H). LC-MS: m/z 490.2 (M+H)+.

Compound 396 (General Procedure 1, Step I)(R)-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-6′-piperazin-1-yl-[3,3′]bipyridinyl-5-carbonitrile

1H NMR (CHLOROFORM-d) 8.201-8.207 (d, J=2.4 Hz, 1H), 7.531 (s, 2H),6.718-6.739 (d, J=8.4 Hz, 1H), 4.867 (m, 1H), 4.477-4.507 (m, 4H),4.149-4.302 (m, 3H), 4.17-4.39 (m, 3H), 3.601-3.807 (m, 6H), 3.494-3.549(m, 1H), 3.349 (s, 3H), 2.992-3.213 (m, 6H), 2.531-2.734 (m, 2H),1.974-2.030 (m, 1H), 1.352-1.367 (d, J=6 Hz, 1H), 1.235-1.265 (t, 2H),0.967-0.992 (m, 2H). LC-MS: m/z 490.2 (M+H)+.

Compound 406 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-[3-(1H-pyrazol-4-yl)-phenyl]-nicotinonitrile

1H NMR (CHLOROFORM-d) 8.030 (s, 2H), 7.735 (s, 1H), 7.589-7.613 (m, 2H),7.423-7.462 (m, 1H), 7.242-7.269 (m, 1H), 4.781 (m, 0.5H), 4.376-4.441(m, 1H), 4.131-4.243 (m, 2H), 3.908-3.940 (d, J=12.8 Hz, 1H),3.660-3.675 (m, 2H), 3.540-3.602 (m, 0.5H), 3.334 (s, 3H), 3.253-3.262(d, J=3.6 Hz, 0.5H), 3.122-3.183 (t, 1H), 2.966-3.022 (t, 0.5H),2.631-2.810 (m, 1H), 2.586-2.615 (m, 1H), 2.061-2.124 (m, 1H),1.362-1.379 (d, J=6.8 Hz, 1H), 1.249-1.266 (d, J=6.8 Hz, 2H),1.165-1.182 (m, 2H), 0.900-0.970 (m, 2H) 137. LC-MS: m/z 471.2 (M+H)+.

Compound 363 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-[3-(1H-pyrazol-3-yl)-phenyl]-nicotinonitrile

¹H NMR (CHLOROFORM-d) 7.820-7.824 (d, J=1.6 Hz, 1H), 7.767-7.795 (t,2H), 7.686-7.692 (d, J=2.4 Hz, 1H), 7.490-7.528 (t, 1H), 7.374-7.393 (d,J=7.6 Hz, 1H), 6.720-6.725 (d, J=2 Hz, 1H), 4.790 (m, 0.5H), 4.396-4.452(m, 1H), 4.153-4.264 (m, 2H), 3.920-3.953 (d, J=13.2 Hz, 0.5H),3.608-3.680 (m, 2H), 3.554-3.582 (t, 0.5H), 3.337 (s, 3H), 3.220 (m,0.5H), 3.140-3.197 (t, 1H), 2.986-3.043 (t, 0.5H), 2.751-2.803 (m, 1H),2.591-2.729 (m, 1H), 2.069-2.120 (m, 1H), 1.372-1.388 (d, J=6.4 Hz, 1H),1.259-1.276 (d, J=6.8 Hz, 2H), 1.156-1.191 (m, 2H), 0.982 (m, 2H).LC-MS: m/z 471.4 (M+H)+.

Compound 436 (General Procedure 1, Step I)(R)-6-cyclopropyl-5-imidazo[1,2-a]pyridin-6-yl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (CHLOROFORM-d) 8.126 (s, 1H), 7.952 (bs, 1H), 7.681-7.684 (d,J=1.2 Hz, 1H), 7.621 (s, 1H), 7.547 (s, 1H), 7.257-7.280 (d, J=13.6 Hz,1H), 4.823 (br, 0.5H), 4.436-4.467 (d, J=12.4 Hz, 0.5H), 4.149-4.278 (m,3H)), 3.649-3.717 (m, 2.5H), 3.446-3.501 (m, 0.5H), 3.299 (s, 3H),3.219-3.254 (m, 1H), 3.019-3.121 (m, 2H), 2.628-2.646 (m, 1H),2.501-2.531 (m, 1H), 1.842-1.897 (m, 1H), 1.293-1.308 (d, J=6 Hz, 1.5H),1.183-1.204 (d, J=8.4 Hz, 1.5H), 1.097-1.115 (m, 2H), 0.902-0.933 (m,2H). LC-MS: m/z 445.1 (M+H)+.

Compound 437 (General Procedure 1, Step I)(R)-5-benzo[1,2,5]oxadiazol-4-yl-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (CHLOROFORM-d) 7.785-7.808 (d, J=9.2 Hz, 1H), 7.646 (s, 1H),7.433-7.473 (d, J=16 Hz, 1H), 7.335-7.353 (dd, J=7.2 Hz, 1H), 4.835 (m,0.5H), 4.441 (m, 0.5H), 4.201-4.320 (m, 3H)), 3.669-3.725 (m, 2.5H),3.478-3.487 (m, 0.5H), 3.312 (s, 3H), 3.103-3.106 (m, 1H), 3.402-3.705(m, 2H), 2.596-2.654 (m, 1H), 2.484-2.537 (m, 1H), 1.769-1.800 (m, 1H),1.308 (m, 1.5H), 1.204-1.219 (d, J=6 Hz, 1.5H), 1.127-1.145 (m, 2H),0.870-0.889 (m, 2H). LC-MS: m/z 447.1 (M+H)+.

Compound 438 (General Procedure 1, Step I)(R)-6-cyclopropyl-5-(1H-indazol-4-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (CHLOROFORM-d) 7.887 (bs, 1H), 7.646 (s, 1H), 7.462-7.483 (d,J=8.4 Hz, 1H), 7.391-7.429 (t, J=15.2 Hz, 1H), 7.055-7.071 (d, J=6.4 Hz,1H), 4.859 (m, 0.5H), 4.465-4.500 (d, J=14 Hz, 0.5H), 4.166-4.281 (m,3H)), 3.671-3.733 (m, 2.5H), 3.486-3.510 (m, 0.5H), 3.312 (s, 3H),3.200-3.252 (m, 1H), 2.992-3.103 (m, 2H), 2.614-2.670 (m, 1H),2.527-2.557 (m, 1H), 1.819-1.840 (m, 1H), 1.340-1.355 (d, J=6 Hz, 1.5H),1.238-1.253 (d, J=6 Hz, 1.5H), 1.101-1.117 (m, 2H), 0.819-0.846 (m, 2H).LC-MS: m/z 445.1 (M+H)⁺.

Compound 473 (General Procedure 1, Step I)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-nicotinonitrile

1H NMR (CHLOROFORM-d) 8.492 (s, 1H), 7.568-7.569 (d, J=0.4 Hz, 1H),7.277 (s, 1H), 7.121-7.125 (t, 1H), 7.064-7.068 (d, J=1.6 Hz, 1H),6.720-6.725 (d, J=2 Hz, 1H), 4.897 (m, 0.5H), 4.510-4.549 (m, 0.5H),4.175 (m, 2.5H), 3.780 (m, 2.5H), 3.543 (t, 0.5H), 3.369 (s, 3H),3.246-3.273 (m, 1H), 3.113-3.119 (m, 1H), 3.019-3.048 (t, 0.5H),2.649-2.759 (m, 1H), 2.556-2.609 (m, 1H), 1.998-2.006 (m, 1H),1.268-1.387 (m, 3H), 1.129-1.155 (m, 2H), 0.928-0.955 (m, 2H). LC-MS:m/z 462.1 (M+H)+.

Compound 474 (General Procedure 1, Step I)(R)-6-cyclopropyl-5-(1-methoxy-isoquinolin-4-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

¹H NMR (CHLOROFORM-d) 8.350-8.325 (d, J=10 Hz, 1H), 7.913 (s, 1H),7.660-7.415 (m, 4H), 4.915 (s, 0.5H), 4.562-4.530 (m, 0.5H), 4.278-4.228(m, 2.5H), 4.261 (s, 3H), 3.797-3.553 (m, 3H), 3.797 (s, 3H),3.577-3.044 (m, 2.5H), 2.750-2.568 (m, 2H), 1.633-1.625 (m, 1H),1.429-1.322 (m, 3H), 1.137-1.093 (m, 2H), 0.842-0.765 (m, 2H). LC-MS:m/z 486.1 (M+H)⁺.

Compound 299(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(4-fluorophenyl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.10-7.16 (m, 4H), 4.62-4.65 (m, 0.5H), 4.23 (d,J=12.8 Hz, 1H), 4.15 (d, J=12.5 Hz, 1H), 4.04 (d, J=8.3 Hz, 0.5H),3.61-3.88 (m, 3.5H), 3.31-3.38 (m, 3H), 3.25 (br. s., 0.5H), 3.02-3.17(m, 1H), 2.89-3.02 (m, 1H), 2.51-2.73 (m, 2H), 2.09-2.18 (m, 3H),1.53-1.59 (m, 1H), 1.33-1.44 (m, 1H), 0.99-1.08 (m, 2H), 0.75-0.86 (m,2H), 0.29-0.63 (m, 4H)

LC-MS: m/z 463.4 (M+H)⁺

Compound 300(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(4-fluorophenyl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.19 (d, J=7.3 Hz, 4H), 4.70 (br. s., 0.5H),4.30 (d, J=13.1 Hz, 1H), 4.18-4.27 (m, 1H), 4.12 (d, J=8.3 Hz, 0.5H),3.81-3.94 (m, 1H), 3.66-3.78 (m, 1H), 3.32 (q, J=9.8 Hz, 2H), 3.08-3.21(m, 1H), 2.97-3.08 (m, 1H), 2.14-2.25 (m, 3H), 1.58-1.67 (m, 1H), 1.50(br. s., 1H), 1.04-1.14 (m, 2H), 0.81-0.89 (m, 2H), 0.65 (br. s., 1H),0.56 (br. s., 1H), 0.37-0.52 (m, 2H)

LC-MS: m/z 487.2 (M+H)⁺

Compound 627(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(6-vinylpyrimidin-4-yl)nicotinonitrile

1H NMR (CHLOROFORM-d) δ 9.30 (d, J=1.1 Hz, 1H), 9.30 (d, J=1.1 Hz, 1H),7.32 (t, J=4.5 Hz, 1H), 6.82 (dd, J=17.4, 10.7 Hz, 1H), 6.64-6.49 (m,1H), 5.81 (dd, J=14.9, 4.1 Hz, 1H), 4.93 (d, J=17.7 Hz, 1H), 4.53 (d,J=13.3 Hz, 1H), 4.20 (dd, J=33.1, 13.9 Hz, 2H), 3.77 (dd, J=18.0, 11.5Hz, 2H), 3.57 (dd, J=12.8, 9.6 Hz, 1H), 3.39 (s, 3H), 3.34-2.95 (m, 3H),2.82-2.49 (m, 2H), 2.26 (s, 3H), 2.88-1.49 (m, 8H), 1.57 (ddd, J=12.5,8.0, 4.5 Hz, 1H), 1.45-1.37 (m, 2H), 1.33-1.28 (m, 2H), 1.14 (dt, J=7.4,3.5 Hz, 2H), 0.96-0.81 (m, 3H).

LC-MS: m/z 447.2 (M+H)⁺

Compound 628(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

1H NMR (CHLOROFORM-d) δ 8.70 (d, J=4.9 Hz, 1H), 7.23 (s, 1H), 7.08 (d,J=4.1 Hz, 1H), 6.88 (dd, J=17.4, 10.8 Hz, 1H), 6.30 (d, J=17.4 Hz, 1H),5.58 (d, J=10.9 Hz, 1H), 4.92 (s, 1H), 4.53 (t, J=14.2 Hz, 1H),4.29-4.08 (m, 3H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (dd, J=23.8, 17.1 Hz,1H), 3.40 (s, 3H), 3.31-2.95 (m, 3H), 2.68 (ddd, J=33.7, 17.4, 11.1 Hz,2H), 2.20 (d, J=8.0 Hz, 3H), 1.57 (ddd, J=12.5, 8.1, 4.6 Hz, 1H), 1.41(d, J=6.3 Hz, 2H), 1.36-1.25 (m, 4H), 1.10 (s, 2H), 0.94-0.74 (m, 3H).

LC-MS: m/z 446.2 (M+H)⁺

Compound 411(R)-5-(4-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

1H NMR (CHLOROFORM-d) d: 6.97-7.10 (m, 2H), 6.87-6.97 (m, J=8.0 Hz, 2H),4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.23 (br. s., 0.5H),3.95-4.18 (m, 2H), 3.71-3.83 (m, 2.5H), 3.58 (m, 0.5H) 3.40 (s, 3H),3.11-3.27 (m, 1.5H), 2.88-3.10 (m, 1H), 2.53-2.82 (m, 2H), 2.16-2.28 (m,3H), 1.68-1.78 (m, 1H), 1.38-1.47 (m, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H),0.98-1.13 (m, 2H), 0.75-0.93 (m, 2H)

LC-MS: m/z 433.5 (M+H)⁺

Compound 278(R)-6-cyclopropyl-5-(6-methoxynaphthalen-2-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.83 (d, J=8.3 Hz, 1H), 7.71-7.78 (m, 1H), 7.60(s, 1H), 7.25-7.32 (m, 1H), 7.17-7.24 (m, 2H), 4.92 (br. s., 0.5H), 4.55(d, J=13.3 Hz, 0.5H), 4.05-4.21 (m, 2.5H), 3.91-4.00 (m, 3H), 3.69-3.87(m, 2.5H), 3.52-3.69 (m, 0.5H), 3.33-3.46 (m, 3H), 3.13-3.29 (m, 1.5H),2.97-3.11 (m, 1H), 2.65-2.83 (m, 1H), 2.60 (dd, J=13.1, 6.5 Hz, 1H),2.17-2.28 (m, 3H), 1.61-1.74 (m, 1H), 1.39-1.49 (m, 1.5H), 1.33 (d,J=6.5 Hz, 1.5H), 0.99-1.17 (m, 2H), 0.69-0.84 (m, 2H)

LC-MS: m/z 499.1 (M+H)⁺

Compound 282(R)-6-cyclopropyl-5-(2-fluorobiphenyl-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.61 (d, J=8.0 Hz, 2H), 7.44-7.57 (m, 3H),7.37-7.44 (m, 1H), 7.00-7.10 (m, 2H), 4.91 (br. s., 0.5H), 4.54 (d,J=13.1 Hz, 0.5H), 4.04-4.32 (m, 2.5H), 3.69-3.89 (m, 2.5H), 3.58 (t,J=10.8 Hz, 0.5H), 3.34-3.42 (m, 3H), 3.12-3.30 (m, 1.5H), 2.93-3.12 (m,1H), 2.64-2.82 (m, 1H), 2.59 (dd, J=13.3, 6.5 Hz, 1H), 2.25 (s, 3H),1.66-1.76 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H),1.04-1.15 (m, 2H), 0.87 (dt, J=7.5, 3.7 Hz, 2H)

LC-MS: m/z 513.1 (M+H)⁺

Compound 318 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(3-methyl-pyridyl-5-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-nicotinonitrile

1H NMR (METHANOL-d) δ 8.79 (s, 1H), 8.70 (s, 1H), 8.40 (d, J=0.4 Hz,1H), 4.77-4.79 (m, 0.5H), 4.42 (d, J=14.4 Hz, 1H), 4.22-4.24 (m, 1.5H),4.14 (d, J=13.2 Hz, 0.5H), 3.94 (d, J=13.2 Hz, 0.5H), 3.68 (t, J=6.0 Hz,2H), 3.55-3.62 (m, 0.5H), 3.31-3.33 (m, 3H), 3.13-3.22 (m, 1H),3.00-3.06 (m, 0.5H), 2.68-2.82 (m, 1H), 2.58-2.63 (m, 4H), 2.22 (s, 3H),1.47-1.54 (m, 1H), 1.37 (d, J=6.8 Hz, 1H), 1.26 (d, J=11.2 Hz, 2H),1.13-1.17 (m, 2H), 0.91-0.94 (m, 2H)

LC-MS: m/z 434.2 (M+H)+.

Compound 319 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(4-methanesulfonyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

¹H NMR (METHANOL-d) d 8.07 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.34 (s,3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H),1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H)

LC-MS: m/z 497.2 (M+H)⁺

Compound 320 (General Procedure 6, Step G′)(R)-2-cyclopropyl-2′-methoxy-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-[3,3′]bipyridinyl-5-carbonitrile

1H NMR (METHANOL-d) δ 8.22 (dd, J1=2.0 Hz, J2=4.8 Hz, 1H), 7.54 (dd,J1=2.0 Hz, J2=7.2 Hz, 1H), 7.07-7.10 (m, 1H), 4.78 (s, 0.5H), 4.38-4.45(m, 1H), 4.01-4.13 (m, 2H), 3.88-3.94 (m, 3.5H), 3.66-3.69 (m, 2H),3.55-3.61 (m, 0.5H), 3.33 (s, 3H), 3.09-3.25 (m, 2H), 2.91-2.97 (m,0.5H), 2.69-2.78 (m, 1H), 2.60-2.64 (m, 1H), 2.12 (s, 3H), 1.49-1.52 (m,1H), 1.40 (d, J=6.4 Hz, 1.3H), 1.28 (dd, J1=2.4 Hz, J2=6.4 Hz, 1.7H),0.99-1.10 (m, 2H), 0.80-0.83 (m, 2H)

LC-MS: m/z 450.2 (M+H)⁺

Compound 321 (General Procedure 6, Step G′)(R)-5-(3-cyano-4-fluoro-phenyl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.71 (dd, J1=2.0 Hz, J2=6.4 Hz, 1H), 7.60-7.64 (m,1H), 7.50 (t, J=9.2 Hz, 1H), 4.77-4.79 (m, 0.5H), 4.38-4.44 (m, 1H),4.05-4.16 (m, 2H), 3.93 (d, J=13.6 Hz, 0.5H), 3.67-369 (m, 2H),3.57-3.58 (m, 0.5H), 3.33 (s, 3H), 3.21-3.28 (m, 1H), 3.11-3.15 (m, 1H),2.96-2.97 (m, 0.5H), 2.69-2.77 (m, 1H), 2.59-2.65 (m, 1H), 2.17 (s, 3H),1.50-1.54 (m, 1H), 1.38 (d, J=6.4 Hz, 1.3H), 1.26 (d, J=6.8 Hz, 1.7H),1.09-1.10 (m, 2H), 0.84-0.89 (m, 2H)

LC-MS: m/z 462.1 (M+H)⁺

Compound 322 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(3-methoxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.47 (t, J=7.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H),7.20 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 4.79 (s, 0.5H), 4.50 (s, 2H),4.37-4.45 (m, 1H), 4.01-4.12 (m, 2H), 3.93 (d, J=13.6 Hz, 0.5H),3.66-3.69 (m, 2H), 3.55-3.62 (m, 0.6H), 3.39 (s, 3H), 3.33 (s, 3H),3.04-3.29 (m, 2H), 2.90-2.97 (m, 0.5H), 2.59-2.81 (m, 2H), 2.15 (s, 3H),1.62-1.66 (m, 1H), 1.42 (d, J=6.4 Hz, 1.4H), 1.31 (d, J=6.4 Hz, 1.6H),1.02-1.09 (m, 2H), 0.77-0.84 (m, 2H)

LC-MS: m/z 463.2 (M+H)⁺

Compound 323 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(3-fluoro-4-methoxy-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.19 (t, J=8.4 Hz, 1H), 6.95-6.99 (m, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H),0.78-0.85 (m, 2H)

LC-MS: m/z 467.2 (M+H)⁺

Compound 324 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(2-fluoro-3-methoxy-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.25-7.34 (m, 2H), 6.75-6.79 (m, 1H), 4.75-4.85(m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H),3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H),2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m,2H)

LC-MS: m/z 467.2 (M+H)+.

Compound 325 (General Procedure 6, Step G′)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-5-(1-methyl-1H-indol-5-yl)-nicotinonitrile

1H NMR (METHANOL-d) δ 7.45 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.21 (s,1H), 6.96 (d, J=8.4 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85(m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41(m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m/z 472.2 (M+H)+.

Compound 326 (General Procedure 6, Step G′)(R)—N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-phenyl)-acetamide

1H NMR (METHANOL-d) δ 7.66 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 2.15 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09(m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m/z 476.2 (M+H)+.

Compound 327 (General Procedure 6, Step G′)(R)-3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-N-methyl-benzamide

1H NMR (METHANOL-d) δ 7.87 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.56-7.62(m, 1H), 7.41 (d, J=8.0 Hz, 1H) 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 3.5H), 2.68-2.85(m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41(m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m/z 476.2 (M+H)+.

Compound 329 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(3-methanesulfonyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 8.02 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 7.75-7.79(m, 1H), 7.61 (d, J=7.6 Hz, 1H) 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 5H), 2.87-2.98 (m, 0.5H), 2.68-2.85(m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41(m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m/z 497.1 (M+H)+.

Compound 330 (General Procedure 6, Step G′)(R)—N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-benzyl)-methanesulfonamide

¹H NMR (METHANOL-d) δ 7.51 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 3.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H),0.78-0.85 (m, 2H).

LC-MS: m/z 526.2 (M+H)+.

Compound 331 (General Procedure 6, Step G′)(R)-4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-N-methyl-benzenesulfonamide

¹H NMR (METHANOL-d) δ 7.95 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.16-3.25(m, 1.5H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 4H),2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H),0.78-0.85 (m, 2H).

LC-MS: m/z 512.2 (M+H)⁺.

Compound 332 (General Procedure 6, Step G′)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-nicotinonitrile

1H NMR (METHANOL-d) δ 7.57-7.59 (m, 2H), 7.40 (s, 1H), 7.34-7.37 (m,2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H),3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.45-3.62 (m, 4.5H), 3.34 (s,3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H),1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z516.2 (M+H)⁺.

Compound 333 (General Procedure 6, Step G′)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-5-[4-(pyrrolidine-1-carbonyl)-phenyl]-nicotinonitrile

¹H NMR (METHANOL-d) δ 7.65 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 4.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H),1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m/z 516.2 (M+H)+.

Compound 335 (General Procedure 6, Step G′)(R)—N-(3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-benzyl)-methanesulfonamide

¹H NMR (METHANOL-d) δ 7.42-7.50 (m, 2H), 7.26 (s, 1H), 7.22 (d, J=7.2Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.31 (s, 2H), 4.05-4.12(m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H),3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.87 (s, 3H),2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H),1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z526.2 (M+H)⁺.

Compound 336 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(4-cyclopropylmethoxy-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

¹H NMR (METHANOL-d) δ 7.11 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.88-4.12 (m, 5H), 3.65-3.72 (m,2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m,1H), 1.21-1.41 (m, 4H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H), 0.61-0.69(m, 2H), 0.35-0.41 (m, 2H).

LC-MS: m/z 489.2 (M+H)+.

Compound 337 (General Procedure 6, Step G′)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-5-(4-propoxy-phenyl)-nicotinonitrile

1H NMR (METHANOL-d) δ 7.10 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.98-4.12 (m, 4H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 1.78-1.89 (m, 2H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H),1.05-1.09 (m, 5H), 0.78-0.85 (m, 2H).

LC-MS: m/z 477.2 (M+H)+.

Compound 340 (General Procedure 6, Step G′)(R)—N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-benzyl)-acetamide

1H NMR (METHANOL-d) δ 7.41 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 2.01 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09(m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m/z 490.1 (M+H)+.

Compound 346 (General Procedure 6, Step G′)(R)-5-(4-fluoro-pyridyl-3-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 8.10-8.09 (d, J=2.4 Hz, 1H), 7.89-7.85 (m, 1H),7.23-7.20 (m, 1H), 4.79-4.78 (d, J=1.2 Hz, 0.5H), 4.44-4.41 (d, J=14 Hz,1H), 4.18-4.01 (m, 2H), 3.95-3.92 (d, J=13.6 Hz, 0.5H), 3.68-3.67 (d,J=5.6 Hz, 2H), 3.62-3.56 (t, J=11.6 Hz, 0.5H), 3.33 (s, 3H), 3.26-3.24(m, 1H), 3.20-3.11 (m, 1H), 3.01-2.98 (m, 0.5H), 2.80-2.69 (m, 1H),2.64-2.59 (m, 1H), 2.19 (s, 3H), 1.56-1.54 (m, 1H), 1.39-1.37 (d, J=6.4Hz, 1H), 1.27-1.26 (d, J=6.8 Hz, 1H), 1.11-1.09 (t, J=3.6 Hz, 2H),0.89-0.87 (m, 2H). LC-MS: m/z 438.1 (M+H)+.

Compound 347 (General Procedure 6, Step G′)(R)-5-(4-cyano-phenyl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.87-7.85 (d, J=8.4 Hz, 2H), 7.47-7.45 (d, J=8 Hz,2H), 4.79 (s, 1H), 4.45-4.39 (m, 1H), 4.16-4.05 (m, 2H), 3.95-3.92 (d,J=13.2 Hz, 0.5H), 3.69-3.66 (t, J=11.6 Hz, 2H), 3.62-3.55 (m, 0.5H),3.33 (s, 3H), 3.27-3.08 (m, 2H), 2.99-2.94 (m, 0.5H), 2.81-2.69 (m, 1H),2.64-2.59 (m, 1H), 2.16 (s, 3H), 1.55-1.49 (m, 1H), 1.39-1.28 (m, 3H),1.12-1.09 (m, 1H), 0.89-0.86 (m, 2H). LC-MS: m/z 444.1 (M+H)+.

Compound 348 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(2-methoxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.53-7.55 (m, 1H), 7.40-7.45 (m, 2H), 7.11-7.14(m, 1H), 4.79 (s, 0.5H), 4.42 (t, J=14.4 Hz, 1H), 4.04-4.15 (m, 4H),3.93 (d, J=12.8 Hz, 0.5H), 3.59-3.69 (m, 2.5H), 3.33 (s, 3H), 3.20 (d,J=4.8 Hz, 4H), 2.95-3.18 (m, 1H), 2.71-2.76 (m, 1H), 2.60-2.65 (m, 1H),2.08 (s, 3H), 1.40-1.5 (m, 2.3H), 1.27-1.38 (m, 1.7H), 1.02-1.09 (m,2H), 0.75-0.82 (m, 2H).

LC-MS: m/z 463.2 (M+H)+.

Compound 349 (General Procedure 6, Step G′)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-5-(2-methyl-2H-pyrazol-3-yl)-nicotinonitrile

1H NMR (METHANOL-d) d 7.60 (s, 1H), 6.33 (s, 1H), 4.75-4.85 (m, 0.5H),4.35-4.48 (m, 1H), 4.21-4.38 (m, 2H), 3.88-3.95 (m, 0.5H), 3.65-3.72 (m,2H), 3.63 (s, 3H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 1H),2.97-3.08 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.19 (m, 2H), 0.78-0.95 (m,2H). LC-MS: m/z 423.2 (M+H)⁺.

Compound 350 (General Procedure 6, Step G′)(R)—N-(3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanesulfonamide

1H NMR (METHANOL-d) d 7.45-7.48 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.11(s, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.98 (s, 3H), 2.87-2.98 (m,0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m,1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z512.1 (M+H)⁺.

Compound 351 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(3,5-dimethyl-isoxazol-4-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) d 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12(m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H),3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),2.57-2.63 (m, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 1.62-1.69(m, 1H), 1.34-1.41 (m, 3H), 1.05-1.12 (m, 2H), 0.85-0.95 (m, 2H).

LC-MS: m/z 438.2 (M+H)⁺.

Compound 358 (General Procedure 6, Step G′)(R)-5-(1-benzyl-1H-pyrazol-4-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) 7.742 (s, 1H), 7.499 (s, 1H), 4.365-7.255 (m, 5H),5.410 (s, 2H), 4.773 (s, 0.5H), 4.429-4.359 (m, 1H), 4.109-4.004 (m,2H), 3.924-3.891 (m, 0.5H), 3.683-3.655 (m, 2H), 3.592-3.535 (m, 0.5H),3.328 (s, 3H), 3.255-3.041 (m, 2H), 2.954-2.898 (m, 0.5H), 2.801-2.588(m, 2H), 2.260 (s, 3H), 1.909-1.869 (m, 1H), 1.375-1.246 (m, 3H), 1.071(s, 2H), 0.90-0.80 (m, 2H). LC-MS: m/z 499.2 (M+H)⁺.

Compound 359 (General Procedure 6, Step G′)

(R)-6-cyclopropyl-5-(2-ethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.40-7.37 (m, 2H), 7.35-7.27 (m, 1H), 7.07-7.04(m, 1H), 4.80-4.79 (d, J=2.4 Hz, 0.5H), 4.46-4.38 (m, 1H), 4.14-4.04 (m,2H), 3.95-3.92 (d, J=12.8 Hz, 0.5H), 3.68-3.63 (m, 2H), 3.60 (m, 0.5H),3.34 (s, 3H), 3.26-3.06 (m, 2H), 2.97-2.94 (d, J=12 Hz, 0.5H), 2.80-2.60(m, 2H), 2.42-2.30 (m, 2H), 2.09 (s, 3H), 1.55-1.50 (m, 1H), 1.43-1.39(m, 1H), 1.32-1.27 (m, 1H), 1.08-1.03 (m, 5.5H) 0.82-0.80 (m, 2H).LC-MS: m/z 447.2 (M+H)+.

Compound 362 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(3-dimethylamino-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.53 (t, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H),7.09 (s, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.78 (s, 1H), 4.38-4.45 (m, 1H),4.03-4.14 (m, 2H), 3.91-3.95 (m, 0.5H), 3.65-3.70 (m, 2H), 3.53-3.62 (m,0.5H), 3.34 (s, 4H), 3.21-3.31 (m, 1.5H), 3.16 (s, 7H), 2.96-2.98 (m,0.5H), 2.71-2.79 (m, 1H), 2.62-2.65 (m, 1H), 2.19 (s, 3H), 1.61-1.67 (m,1H), 1.38-1.40 (d, J=6.4 Hz, 1.3H), 1.27-1.28 (d, J=6.4 Hz, 1.7H),1.07-1.09 (m, 2H), 0.81-0.84 (m, 2H). LC-MS: m/z 462.1 (M+H)+.

Compound 365 (General Procedure 6, Step G′)(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-nicotinonitrile

¹H NMR (METHANOL-d) d 7.64 (s, 1H), 7.44 (s, 1H), 4.75-4.85 (m, 0.5H),4.35-4.48 (m, 1H), 3.88-4.12 (m, 5.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85(m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41(m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 423.1 (M+H)+.

Compound 366 (General Procedure 6, Step G′)(R)-3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-benzoicacid methyl ester

¹H NMR (METHANOL-d) d 8.06 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.58-7.63(m, 1H), 7.48 (d, J=8.0 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85(m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41(m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 477.1 (M+H)+.

Compound 369 (General Procedure 6, Step G′)(R)-2-cyclopropyl-2′-fluoro-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-[3,3′]bipyridinyl-5-carbonitrile

1H NMR (METHANOL-d) δ 8.31-8.30 (d, J=4.4 Hz, 1H), 7.90-7.86 (t, J=8.4Hz, 1H), 7.48-7.45 (m, 1H), 4.82-4.79 (m, 0.5H), 4.45-4.37 (m, 0.5H),4.20-4.10 (m, 2H), 3.95-3.92 (d, J=12.8 Hz, 0.5H), 3.68-3.67 (m, 2H),3.62-3.56 (t, J=12 Hz, 0.5H), 3.34-3.33 (m, 3.5H), 3.18-3.16 (d, J=10.8Hz, 1H), 3.01 (m, 1H), 2.80-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.2 (s,3H), 1.52-1.49 (m, 1H), 1.39-1.38 (d, J=2.8 Hz, 1H), 1.28-1.27 (d, J=6.4Hz, 1H), 1.13-0.90 (m, 1H), 0.90-0.88 (m, 1H). LC-MS: m/z 438.2 (M+H)⁺.

Compound 372 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(2-hydroxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (CHLOROFORM-d) δ 7.61-7.59 (d, J=7.6 Hz, 1H), 7.46-7.37 (m, 2H),7.10-7.08 (d, J=7.2 Hz, 1H), 4.90 (s, 0.5H), 4.53-4.34 (M, 2.5H),4.22-4.05 (m, 2.5H), 3.79-3.71 (m, 2.5H), 3.60-3.54 (M, 0.5H), 3.48 (S,1H), 3.37 (S, 3H), 3.19-3.14 (M, 1.5H), 3.03-2.98 (m, 1H), 2.75-2.66 (M,1H), 2.60-2.55 (m, 1H), 2.11 (s, 3H), 1.48-1.44 (m, 2H), 1.31-1.30 (d,J=4.8 Hz, 1.5H), 1.10-1.07 (m, 2H). LC-MS: m/z 449.1 (M+H)⁺.

Compound 380 (General Procedure 6, Step G′)(R)—N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanesulfonamide

1H NMR (METHANOL-d) d 7.36 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.16-3.25(m, 1.5H), 3.03 (s, 3H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H),1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 512.2 (M+H)+.

Compound 393 (General Procedure 6, Step G′)(R)-4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-pyridin-3-yl}-benzenesulfonamide

1H NMR (METHANOL-d) d 8.02 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H),4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m,0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25(m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18(s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H),0.78-0.85 (m, 2H). LC-MS: m/z 498.1 (M+H)⁺.

Compound 405 (General Procedure 6, Step G′)(R)-6-cyclopropyl-5-(2,3-difluoro-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile

1H NMR (METHANOL-d) δ 7.26-7.39 (m, 2H), 7.07 (t, J=6.8 Hz, 1H), 4.72(s, 0.5H), 4.41-4.45 (m, 1H), 4.07-4.19 (m, 2H), 3.93 (d, J=13.6 Hz,0.5H), 3.66-3.69 (m, 2H), 3.56-3.62 (m, 0.5H), 3.33 (s, 3H), 3.20-3.28(m, 1H), 3.14-3.17 (m, 1H), 2.96-3.02 (m, 0.5H), 2.60-2.81 (m, 2H), 2.18(s, 3H), 1.55-1.61 (m, 1H), 1.38 (d, J=6.4 Hz, 1.3H), 1.27 (d, J=6.8 Hz,1.7H), 1.06-1.1 (m, 2H), 0.82-0.89 (m, 2H). LC-MS: m/z 455.1 (M+H)⁺.

Compound 589(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

It was obtained by the same procedure of Compound 527.

¹H NMR (CHLOROFORM-d) δ 8.70 (d, J=5.0 Hz, 1H), 7.26 (s, 1H), 7.10 (d,J=3.8 Hz, 1H), 6.90 (dd, J=17.4, 10.9 Hz, 1H), 6.32 (d, J=17.3 Hz, 1H),5.61 (d, J=11.3 Hz, 1H), 4.60-4.76 (m, 0.5H), 4.34 (d, J=12.8 Hz, 1H),4.26 (d, J=12.8 Hz, 1H), 4.08 (d, J=9.0 Hz, 0.5H), 3.92 (br. s., 2H),3.78 (br. s., 1H), 3.39-3.56 (m, 1H), 3.23 (br. s., 1H), 3.15 (d, J=11.8Hz, 1H), 3.05 (br. s., 1H), 2.61 (br. s., 2H), 2.17-2.29 (m, 3H),1.55-1.60 (m, 1H), 1.38-1.47 (m, 1H), 1.27-1.33 (br. s., 1H), 1.12 (br.s., 2H), 0.64 (br. s., 2H), 0.33-0.54 (m, 2H)

LC-MS: m/z 458.3 (M+H)⁺

Compound 674(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-vinylpyridazin-4-yl)nicotinonitrile

Step1(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-hydroxypyridazin-4-yl)nicotinonitrile

A mixture of(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(200 mg, 0.42 mmol), 5-chloropyridazin-3-ol (109 mg, 0.625 mmol), CsF(127 mg, 0.84 mmol) and Pd(dppf)Cl₂ (17 mg) in dioxane and water washeated at 100° C. for 2 hrs. The reaction mixture was concentrated andthe residue was purified by pre-TLC to afford 120 mg of title compound.

LC-MS: m/z 449.2 (M+H)⁺

Step 2(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)pyridin-3-yl)pyridazin-3-yltrifluoromethanesulfonate

A solution of(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-hydroxypyridazin-4-yl)nicotinonitrile(120 mg, 0.27 mmol), Tf₂O (100 mg, 0.48 mmol) and TEA (0.1 mL) in DCMwas stirred for 1 hr. The reaction mixture was washed with water, driedand concentrated. The residue was purified by pre-TLC to afford 60 mg oftitle compound.

¹H NMR (CHLOROFORM-d) δ: 9.41 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.51 (d,J=1.8 Hz, 1H), 4.71 (d, J=12.8 Hz, 1.5H), 4.58 (d, J=11.5 Hz, 1H), 4.14(brs, 0.5H), 3.93 (br. s., 0.5H), 3.75 (br. s., 2.5H), 3.39 (s, 3H),3.21-3.36 (m, 3H), 2.54-2.83 (m, 2H), 1.86-1.96 (m, 1H), 1.08-1.28 (m,5H), 0.48-0.63 (m, 4H).

LC-MS: m/z 580.7 (M+H)⁺

Step 3(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-vinylpyridazin-4-yl)nicotinonitrile(Compound 674)

A mixture of(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyppiperazin-1-yl)pyridin-3-yl)pyridazin-3-yltrifluoromethanesulfonate (25 mg, 0.043 mmol), Potassiumvinyltrifluoroborate (12 mg, 0.083 mmol), TEA (20 mg, 0.215 mmol) andPd(dppf)Cl₂(3.5 mg) in i-PrOH and water was heated at 100° C. for 2 hrs.The reaction mixture was concentrated and the residue was purified bypre-TLC to afford 11 mg of title compound.

¹H NMR (CHLOROFORM-d) δ9.21 (br. s., 1H), 7.68 (s, 1H), 7.61 (s, 1H),7.13 (dd, J=17.6, 11.0 Hz, 1H), 6.37 (d, J=17.6 Hz, 1H), 5.79 (d, J=11.0Hz, 1H), 4.63 (d, J=12.8 Hz, 1.5H), 4.50 (d, J=12.3 Hz, 1H), 4.05-4.18(m, 0.5H), 3.90 (d, J=11.0 Hz, 0.5H), 3.63-3.83 (m, 2.5H), 3.38 (s, 3H),3.18-3.33 (m, 2H), 3.15 (br. s., 1H), 2.71-2.64 (m, 2H), 1.89-1.99 (m,1H), 1.29-1.40 (m, 3H), 1.07 (dd, J=7.4, 2.9 Hz, 2H), 0.61-0.44 (m, 4H).

LC-MS: m/z 459.0 (M+H)⁺

Compound 675(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)pyridin-3-yl)pyridazin-3-yltrifluoromethanesulfonate

¹H NMR (CHLOROFORM-d) δ: 9.41 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.51 (d,J=1.8 Hz, 1H), 4.71 (d, J=12.8 Hz, 1.5H), 4.58 (d, J=11.5 Hz, 1H), 4.14(brs, 0.5H), 3.93 (br. s., 0.5H), 3.75 (br. s., 2.5H), 3.39 (s, 3H),3.21-3.36 (m, 3H), 2.54-2.83 (m, 2H), 1.86-1.96 (m, 1H), 1.08-1.28 (m,5H), 0.48-0.63 (m, 4H).

LC-MS: m/z 580.7 (M+H)⁺

Compound 687(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)pyridazin-3-yltrifluoromethanesulfonate

¹H NMR (CHLOROFORM-d) δ: 9.42 (br. s., 1H), 7.72 (s, 1H), 7.52 (s, 1H),4.73 (d, J=12.8 Hz, 1.5H), 4.60 (d, J=12.0 Hz, 1H), 4.33 (brs, 0.5H),4.05 (brs, 0.5H), 3.76 (br. s., 1H), 3.24-3.40 (m, 2.5H), 1.89-1.97 (m,1H), 1.72 (br. s., 1H), 1.29-1.34 (m, 3H), 0.99-1.20 (m, 4H), 0.78-0.90(m, 2H), 0.41-0.66 (m, 4H).

LC-MS: m/z 563.0 (M+H)⁺

Compound 7666-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile

Step1(R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile

A stirred solution of (R)-tert-butyl4-(3-cyano-6-cyclopropyl-5-(5-vinylpyridazin-3-yl)pyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(100 mg, 0.2 mmol) in TFA (2 mL) was stirred at room temperatureovernight. When LC-MS showed completion of the reaction, the mixture wasevaporated under reduced pressure and the residue was dissolved in DCM,washed with Sat. NaHCO3, and brine. The organic layer was evaporatedunder reduced pressure to give crude product which was used withoutfurther purification (70 mg)

Step 2. Compound 766

To a stirred 2-(oxetan-2-yl)acetic acid (20 mg) in CH₂Cl₂ was added HATU(72 mg, 0.19 mmol) followed by DIPEA, the mixture was stirred at roomtemperature for 1 hr, then(R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile(70 mg) was added. The mixture was stirred at room temperatureovernight. It was quenched with water, extracted with CH₂Cl₂. Theorganic layer was washed with Sat. NaHCO3, brine and dried over Na2SO4,evaporated and purified by prepTLC to give product.

¹H NMR (CHLOROFORM-d) δ: 9.23 (br. s., 1H), 7.97 (s, 1H), 7.61 (d, J=1.8Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.76(d, J=10.9 Hz, 1H), 5.11-5.36 (m, 1H), 4.48-4.77 (m, 4H), 4.08 (d, J=8.5Hz, 0.5H), 3.95 (d, J=13.2 Hz, 0.5H), 3.75 (d, J=11.2 Hz, 0.5H), 3.32(br. s., 1H), 3.05-3.27 (m, 2H), 2.98 (dd, J=14.8, 6.0 Hz, 1.5H),2.79-2.90 (m, 2H), 2.54 (d, J=7.9 Hz, 1H), 2.12-2.26 (m, 1H), 1.25 (dd,J=6.6, 3.7 Hz, 3H), 0.94-1.12 (m, 2H), 0.51-0.72 (m, 2H), 0.35-0.49 (m,2H)

LC-MS: m/z 471.6 (M+H)⁺

Compound 769(R,E)-6-cyclopropyl-2-(3-cyclopropyl-4-(5-hydroxypent-2-enoyl)piperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.27 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H),6.87 (dt, J=14.8, 7.3 Hz, 1H), 6.73 (dd, J=17.8, 11.0 Hz, 1H), 6.26-6.48(m, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 4.42 (d,J=12.9 Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 3.89-4.21 (m, 1H), 3.79 (t,J=6.0 Hz, 2H), 3.38 (br. s., 1H), 3.23 (d, J=10.0 Hz, 1H), 3.08 (td,J=12.5, 2.9 Hz, 1H), 2.50 (q, J=6.2 Hz, 2H), 2.18-2.29 (m, 3H),1.36-1.50 (m, 2H), 1.15 (br. s., 2H), 0.88 (dd, J=7.6, 3.2 Hz, 2H), 0.65(br. s., 1H), 0.51 (br. s., 1H), 0.44 (br. s., 2H)

LC-MS: m/z 485.6 (M+H)⁺

Compound 7686-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ:9.28 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H),6.74 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.9 Hz, 1H), 5.71-5.86 (m,1H), 5.27 (quin, J=6.7 Hz, 1H), 4.64-4.76 (m, 1H), 4.49-4.63 (m, 1H),4.41 (d, J=12.6 Hz, 1H), 4.23-4.37 (m, 1H), 4.07 (d, J=8.2 Hz, 1H), 3.92(d, J=12.6 Hz, 1H), 3.69-3.86 (m, 1H), 3.20-3.36 (m, 1H), 2.93-3.20 (m,3H), 2.74-2.93 (m, 2H), 2.46-2.66 (m, 1H), 2.18-2.30 (m, 3H), 1.78 (br.s., 1H), 1.41-1.51 (m, 2H), 1.33-1.41 (m, 1H), 1.10-1.20 (m, 2H), 0.89(dd, J=7.8, 3.1 Hz, 2H), 0.58-0.72 (m, 1H), 0.53 (br. s., 1H), 0.45 (d,J=5.6 Hz, 2H)

LC-MS: m/z 485.6 (M+H)⁺

Compound 767

(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ:9.28 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.28 (s,1H), 6.74 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.78 (d,J=10.9 Hz, 1H), 4.37-4.47 (m, 1H), 4.26-4.36 (m, 1H), 4.01-4.13 (m, 1H),3.83-3.98 (m, 2H), 3.65-3.83 (m, 1H), 3.13-3.29 (m, 2H), 2.98-3.13 (m,1H), 2.46-2.68 (m, 2H), 2.19-2.29 (m, 3H), 1.84-2.10 (m, 1H), 1.42-1.55(m, 1H), 1.15 (br. s., 1H), 0.81-0.95 (m, 3H), 0.63 (br. s., 1H), 0.53(br. s., 1H), 0.32-0.48 (m, 2H)

LC-MS: m/z 459.6 (M+H)⁺

Compound 749(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.21 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.64 (d,J=2.1 Hz, 1H), 7.15 (dd, J=17.8, 11.0 Hz, 1H), 6.39 (d, J=17.9 Hz, 1H),5.81 (d, J=10.9 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.52 (d, J=12.9 Hz,1H), 4.10 (d, J=9.7 Hz, 1H), 3.85-3.99 (m, 2H), 3.71-3.83 (m, 1H),3.07-3.36 (m, 3H), 2.42-2.71 (m, 2H), 1.88-2.02 (m, 1H), 1.20-1.40 (m,3H), 1.01-1.12 (m, 2H), 0.45-0.78 (m, 4H)

LC-MS: m/z 473.3 (M+H)⁺

Compound 724(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.22 (s, 1H), 7.93-8.03 (m, 1H), 7.61 (d, J=1.8Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.76(d, J=10.9 Hz, 1H), 4.65 (d, J=13.2 Hz, 1H), 4.52 (d, J=12.6 Hz, 1H),4.16 (m, 1H), 3.80-4.02 (m, 2H), 3.58-3.74 (m, 1H), 3.45 (s, 3H), 3.26(d, J=10.3 Hz, 2H), 3.12 (t, J=10.6 Hz, 1H), 2.11-2.32 (m, 1H),1.23-1.30 (m, 3H), 0.98-1.08 (m, 2H), 0.41-0.72 (m, 4H)

LC-MS: m/z 445.2 (M+H)⁺

Compound 723(R)-tert-butyl(6-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)pyridin-3-yl)pyridazin-4-yl)carbamate

The mixture of((R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(67 mg, 0.157 mmol), tert-butyl (6-chloropyridazin-4-yl)carbamate (30mg, 0.131 mmol), Pd(dppf)Cl₂ (5 mg, 0.007 mmol) and CsF (40 mg, 0.216mmol) in dioxane/H₂O was stirred at 100° C. for 16 hours. The mixturewas diluted with EtOAc (30 mL) and filtered. The filtrated waspartitioned between EtOAc (30 mL) and water (10 mL), the organic layerwas washed with water (10 mL), brine and dried over Na₂SO₄ andconcentrated to give the crude which was purified by prep-TLC to give 20mg of the product.

¹H NMR (CHLOROFORM-d) δ: 9.08 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.60(br. s., 1H), 4.64 (d, J=12.9 Hz, 1H), 4.52 (d, J=12.3 Hz, 1H), 4.08 (d,J=8.5 Hz, 1H), 3.93 (s, 2H), 3.66-3.84 (m, 1H), 3.25 (m, 3H), 2.50-2.61(m, 2H), 1.56 (s, 9H), 1.21-1.28 (m, 3H), 1.07 (s, 2H), 0.41-0.80 (m,4H)

LC-MS: m/z 534.3 (M+H)⁺

Compound 716(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ9.23 (s, 1H), 7.98 (s, 1H), 7.61 (d, J=2.1 Hz,1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.71-5.84(m, 1H), 4.64 (d, J=12.9 Hz, 1H), 4.51 (d, J=12.6 Hz, 1H), 4.01-4.16 (m,1H), 3.92 (s, 2H), 3.65-3.83 (m, 1H), 3.05-3.25 (d, J=11.2 Hz, 2H),2.50-2.68 (m, 2H), 2.12-2.30 (m, 1H), 1.19-1.27 (m, 3H), 1.00-1.11 (m,2H), 0.39-0.62 (m, 1H)

LC-MS: m/z 445.2 (M+H)⁺

Compound 715(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(6-vinylpyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ9.20 (s, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.11(dd, J=17.8, 11.0 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.77 (d, J=11.2 Hz,1H), 4.64 (d, J=12.9 Hz, 1H), 4.50 (d, J=12.6 Hz, 1H), 4.15 (s, 2H),3.80-4.12 (m, 1H), 3.60-3.66 (m, 1H), 3.44 (s, 3H), 3.26 (dd, J=13.2,3.5 Hz, 1H), 3.07-3.18 (m, 1H), 1.87-2.04 (m, 1H), 1.19-1.29 (m, 3H),1.06 (dd, J=7.9, 2.9 Hz, 2H), 0.47-0.65 (m, 4H)

LC-MS: m/z 445.2 (M+H)⁺

Compound 696(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.23 (d, J=2.1 Hz, 1H), 7.98 (s, 1H), 7.63 (d,J=2.1 Hz, 1H), 6.75 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H),5.78 (d, J=10.9 Hz, 1H), 4.66 (d, J=12.9 Hz, 2.5H), 3.98-4.54 (m, 1H),3.51-3.88 (m, 1H), 3.00-3.45 (m, 1H), 2.16-2.28 (m, 1H), 1.72 (s, 1H),1.17-1.30 (m, 3H), 0.95-1.11 (m, 4H), 0.77-0.87 (m, 2H), 0.39-0.64 (m,1H)

LC-MS: m/z 441.2 (M+H)⁺

Compound 686(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(6-vinylpyridazin-4-yl)nicotinonitrile

The mixture of(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(100 mg, 0.235 mmol), 5-chloro-3-vinylpyridazine (30 mg, 0.213 mmol),Pd(dppf)Cl₂ (8 mg, 0.011 mmol) and CsF (98 mg, 0.640 mmol) indioxane/H₂O was stirred at 100° C. for 16 hours. The mixture was dilutedwith EtOAc (30 mL) and filtered. The filtrate was partitioned betweenEtOAc (30 mL) and water (10 mL), the organic layer was washed with water(10 mL), brine, dried over Na₂SO₄ and concentrated to give the crudewhich was purified by prep-TLC to give 25 mg of the product.

¹H NMR (CHLOROFORM-d) δ: 9.21 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.64 (d,J=2.1 Hz, 1H), 7.15 (dd, J=17.8, 11.0 Hz, 1H), 6.39 (d, J=17.9 Hz, 1H),5.81 (d, J=10.9 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.52 (d, J=12.9 Hz,1H), 4.10 (d, J=9.7 Hz, 1H), 3.87-4.01 (m, 2H), 3.71-3.87 (m, 1H),3.07-3.36 (m, 3H), 2.46-2.70 (m, 2H), 1.81-2.03 (m, 1H), 1.20-1.34 (m,3H), 1.03-1.13 (m, 2H), 0.60-0.69 (m, 1H), 0.46-0.57 (m, 4H)

LC-MS: m/z 445.2 (M+H)⁺

Compound 671(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(6-hydroxypyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 12.36 (br. s., 1H), 7.95 (d, J=2.0 Hz, 1H),7.65 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.50 (d,J=12.8 Hz, 1H), 4.01-4.19 (m, 1H), 3.89-3.98 (m, 2H), 3.60-3.85 (m, 1H),3.01-3.29 (m, 3H), 2.60 (dd, J=11.8, 6.0 Hz, 2H), 1.87-2.05 (m, 1H),1.14-1.26 (m, 3H), 0.31-1.14 (m, 4H).

LC-MS: m/z 435.2 (M+H)⁺

Compound 673(R)-6′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-2′,5-dicarbonitrile

The mixture of(R)-2′,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile(40 mg, 0.084 mmol), CuCN (15 mg, 0.169 mmol), CuI (1 mg) in NMP (2 mL)was stirred at 230° C. for 2 hours. After cooling to room temperature,the mixture was partitioned between EtOAc (30 mL) and water (10 mL), theorganic layer was washed with water (10 mL), brine and dried overNa2SO4, concentrated to give the crude which was purified by prep-TLC togive 20 mg of the product.

¹H NMR (CHLOROFORM-d) δ: 7.72 (d, J=1.0 Hz, 1H), 7.59-7.66 (m, 2H), 4.91(s, 0.5H), 4.54 (d, J=10.3 Hz, 0.5H), 4.24-4.48 (m, 2.5H), 3.69-3.79 (m,2H), 3.51-3.62 (m, 0.5H), 3.33-3.44 (m, 4H), 3.18-3.29 (m, 1.5H),3.10-3.25 (m, 1.5H), 2.63-2.82 (m, 1H), 2.52-2.63 (m, 1H), 1.82-1.95 (m,1H), 1.36 (d, J=6.5 Hz, 1H), 1.23-1.28 (m, 4H), 1.04-1.15 (m, 2H)

LC-MS: m/z 465.2 (M+H)⁺

Compound 672(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-6′-vinyl-[3,4′-bipyridine]-2′,5-dicarbonitrile

The mixture of(R)-6′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-2′,5-dicarbonitrile(10 mg, 0.0215 mmol), Potassium vinyltrifluoroborate (5 mg, 0.032 mmol),Pd(dppf)Cl₂ (1 mg, 0.001 mmol) and CsF (10 mg, 0.064 mmol) indioxane/H₂O was stirred at 100° C. for 16 hours. The mixture was dilutedwith EtOAc (30 mL) and filtered. The filtrated was partitioned betweenEtOAc (30 mL) and water (10 mL), the organic layer was washed with water(10 mL), brine and dried over Na₂SO₄ and concentrated to give the crudewhich was purified by prep-TLC to give 5 mg of the product.

¹H NMR (CHLOROFORM-d) δ: 7.63 (s, 2H), 7.52-7.59 (m, 1H), 6.86 (dd,J=17.4, 10.7 Hz, 1H), 6.42 (d, J=17.6 Hz, 1H), 5.71 (d, J=10.8 Hz, 1H),4.92 (s, 0.5H), 4.54 (d, J=9.5 Hz, 0.5H), 4.25-4.46 (m, 2.5H), 3.71-3.86(m, 3.5H), 3.35-3.42 (m, 3.5H), 3.03-3.29 (m, 1.5H), 2.63-2.82 (m, 1H),2.53-2.62 (m, 1H), 1.83-1.96 (m, 1H), 1.34-1.40 (m, 2H), 1.20-1.26 (m,3H), 1.00-1.11 (m, 2H).

LC-MS: m/z 457.2 (M+H)⁺

Compound 653(R)-2-cyclopropyl-2′-(3-hydroxyprop-1-en-2-yl)-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile

Step1(R)-2-cyclopropyl-2′-hydroxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile

A mixture of(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(100 mg, 0.22 mmol), 4-bromopyridin-2-ol (38 mg, 0.22 mmol), CsF (66 mg,0.44 mmol) and Pd(dppf)Cl₂ (5 mg) in dioxane and water was heated at100° C. for 0.5 hr. The reaction mixture was concentrated and theresidue was purified by pre-TLC to afford 52 mg of title compound.

LC-MS: m/z 422.1 (M+H)⁺

Step 2(R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridin]-2′-yltrifluoromethanesulfonate

A solution of(R)-2-cyclopropyl-2′-hydroxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile(100 mg, 0.24 mmol), Tf₂O (40 mg) and TEA (1 drop) in DCM (5 ml) wasstirred for 1 hr. The reaction mixture was washed with water, dried andconcentrated. The residue was purified by pre-TLC to afford 60 mg oftitle compound.

LC-MS: m/z 554.1 (M+H)⁺

Step 3(R)-2-cyclopropyl-2′-(3-hydroxyprop-1-en-2-yl)-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrileCompound 653

A mixture of(R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridin]-2′-yltrifluoromethanesulfonate (150 mg, 0.27 mmol), prop-2-en-1-ol (31 mg,0.54 mmol), TEA (30 mg, 0.30 mmol), Pd(OAc)₂(15 mg, 0.0675 mmol), andDppf (72 mg, 0.13 mmol) in DMF (10 mL) was heated at 100° C. for 2 hrs.The reaction mixture was diluted with DCM and washed with water andbrine, dried and concentrated and the residue was purified by prep-TLCand prep-HPLC to afford 16 mg of title compound.

¹H NMR (CHLOROFORM-d) δ8.62 (d, J=5.3 Hz, 1H), 7.69 (s, 1H), 7.65 (s,1H), 7.31 (dd, J=5.0, 1.3 Hz, 1H), 5.87 (s, 1H), 5.60 (s, 1H), 4.92(brs, 0.5H), 4.65 (s, 2H), 4.54 (d, J=12.5 Hz, 0.5H), 4.20-4.46 (m,2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.39 (s, 3H), 3.33 (d,J=13.3 Hz, 1H), 3.01-3.27 (m, 1.5H), 2.64-2.85 (m, 1H), 2.51-2.64 (m,1H), 1.96-2.08 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.25-1.36 (m, 1.5H),1.17-1.25 (m, 2H), 0.95-1.09 (m, 2H).

LC-MS: m/z 462.1 (M+H)⁺

Compound 7656-cyclopropyl-2-((R)-3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methyl-5-(2-vinylquinoxalin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.00 (s, 1H), 8.09-8.21 (m, 1H), 7.80-7.91 (m,1H), 7.53-7.66 (m, 1H), 7.00-7.13 (m, 1H), 6.51 (d, J=17.6 Hz, 1H), 5.85(d, J=11.2 Hz, 1H), 4.71 (d, J=10.0 Hz, 0.5H), 4.47 (d, J=10.3 Hz,0.5H), 4.40 (d, J=13.5 Hz, 1H), 4.23-4.35 (m, 1H), 3.85 (d, J=13.5 Hz,0.5H), 3.71-3.81 (m, 2H), 3.59 (d, J=10.3 Hz, 0.5H), 3.46-3.55 (m,0.5H), 3.40 (d, J=5.0 Hz, 3H), 3.05-3.14 (m, 2H), 3.02 (d, J=9.7 Hz,1H), 2.55-2.83 (m, 3H), 2.28-2.44 (m, 1H), 2.15-2.28 (m, 1H), 2.04-2.10(m, 3H), 1.02-1.12 (m, 6H), 0.84-0.95 (m, 2H), 0.72-0.81 (m, 1H),0.59-0.70 (m, 1H)

LC-MS: m/z 525.6 (M+H)⁺

Compound 7602-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.70 (d, J=4.4 Hz, 1H), 7.25 (s, 1H), 7.09 (d,J=3.5 Hz, 1H), 6.90 (dd, J=17.5, 10.7 Hz, 1H), 6.32 (d, J=17.3 Hz, 1H),5.60 (d, J=10.9 Hz, 1H), 5.22-5.34 (m, 1H), 4.65-4.77 (m, 1H), 4.52-4.63(m, 1H), 4.22-4.41 (m, 2H), 4.09 (d, J=8.2 Hz, 1H), 3.91 (br. s., 1H),3.38 (s, 1H), 3.14 (br. s., 1H), 2.94-3.09 (m, 2H), 2.68-2.94 (m, 3H),2.49-2.63 (m, 1H), 2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12 (br. s., 2H),0.88 (dd, J=7.6, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.55 (br. s., 1H),0.34-0.51 (m, 2H)

LC-MS: m/z 484.7 (M+H)⁺

Compound 7612-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((S)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.70 (d, J=4.4 Hz, 1H), 7.25 (s, 1H), 7.09 (d,J=3.5 Hz, 1H), 6.90 (dd, J=17.5, 10.7 Hz, 1H), 6.32 (d, J=17.3 Hz, 1H),5.60 (d, J=10.9 Hz, 1H), 5.22-5.34 (m, 1H), 4.65-4.77 (m, 1H), 4.52-4.63(m, 1H), 4.22-4.41 (m, 2H), 4.09 (d, J=8.2 Hz, 1H), 3.91 (br. s., 1H),3.38 (s, 1H), 3.14 (br. s., 1H), 2.94-3.09 (m, 2H), 2.68-2.94 (m, 3H),2.49-2.63 (m, 1H), 2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12 (br. s., 2H),0.88 (dd, J=7.6, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.55 (br. s., 1H),0.34-0.51 (m, 2H)

LC-MS: m/z 484.7 (M+H)⁺

Compound 664(R)-2-cyclopropyl-6-(4-(1-hydroxycyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ:8.64 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.40 (s,1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H), 6.27(d, J=17.6 Hz, 1H), 5.57 (d, J=11.3 Hz, 1H), 4.87 (br. s., 1H), 4.50 (d,J=11.8 Hz, 1H), 4.39 (d, J=12.8 Hz, 1H), 4.32 (d, J=11.5 Hz, 1H), 3.32(dd, J=13.1, 2.8 Hz, 1H), 3.21-3.66 (m, 2H), 1.99-2.07 (m, 1H),1.30-1.50 (m, 3H), 1.21 (dt, J=7.2, 3.5 Hz, 2H), 1.11-1.17 (m, 1H),0.91-1.09 (m, 5H).

LC-MS: m/z 430.2 (M+H)⁺

Compound 739 (R)-methyl4-(4-(2′-chloro-5-cyano-2-cyclopropyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazin-1-yl)-4-oxobutanoate

¹H NMR (CHLOROFORM-d) δ:8.48 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.41 (s,1H), 7.30 (d, J=4.4 Hz, 1H), 4.59 (d, J=12.3 Hz, 1H), 4.46 (d, J=12.0Hz, 1H), 4.06 (br. s., 1H), 3.81-3.94 (m, 1H), 3.72 (s, 3H), 3.06-3.36(m, 1.5H), 2.84 (br. s., 1.5H), 2.71 (d, J=7.9 Hz, 3H), 2.50-2.66 (m,1H), 1.91-2.07 (m, 1H), 1.33 (br. s., 1H), 1.27 (br. s., 1H), 1.14-1.25(m, 2H), 1.05 (dd, J=7.5, 3.4 Hz, 2H), 0.61 (br. s., 1H), 0.54 (br. s.,1H), 0.45 (d, J=4.1 Hz, 2H).

LC-MS: m/z 494.2 (M+H)⁺

Compound 738(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-hydroxyacetyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ:8.55-8.78 (m, 1H), 7.66 (s, 1H), 7.39 (br. s.,1H), 7.17-7.26 (m, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.3Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.56 (d, J=12.9 Hz, 1H), 4.43 (d,J=12.9 Hz, 1H), 4.22 (br. s., 1H), 4.18 (br. s., 1H), 4.01 (br. s.,0.5H), 3.68 (br. s., 1.5H), 3.34-3.53 (m, 1H), 3.24 (d, J=10.9 Hz, 1H),3.09 (t, J=11.3 Hz, 1H), 2.00-2.07 (m, 1H), 1.32 (br. s., 1H), 1.27 (br.s., 1H), 1.21 (br. s., 2H), 1.02 (br. s., 2H), 0.66 (br. s., 1H), 0.57(br. s., 1H), 0.48 (br. s., 1H).

LC-MS: m/z 430.2 (M+H)⁺

Compound 747(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(4-methoxybutanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.67 (d, J=4.7 Hz, 1H), 7.66 (s, 1H), 7.46 (br.s., 1H), 7.31 (br. s., 1H), 6.95 (dd, J=17.3, 10.9 Hz, 1H), 6.38 (d,J=17.3 Hz, 1H), 5.66 (d, J=10.6 Hz, 1H), 4.58 (d, J=12.9 Hz, 1H), 4.46(d, J=12.3 Hz, 1H), 3.70-4.12 (br. s., 2H), 3.46 (br. s., 2H), 3.36 (s,3H), 3.23 (br. s., 1H), 3.11 (br. s., 1H), 2.49 (br. s., 2H), 1.89-2.14(m, 4H), 1.27-1.31 (m, 1H), 1.18-1.25 (m, 2H), 1.00-1.08 (m, 2H), 0.59(d, J=15.6 Hz, 2H), 0.47 (d, J=5.0 Hz, 2H).

LC-MS: m/z 472.5 (M+H)⁺

Compound 753(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(4-hydroxybutanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.64 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.39 (s,1H), 7.18-7.27 (m, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.28 (d, J=17.6Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.42 (d,J=12.6 Hz, 1H), 4.09 (d, J=7.9 Hz, 0.5H), 3.86 (d, J=13.2 Hz, 0.5H),3.73 (br. s., 2H), 3.05-3.32 (m, 2H), 2.97 (s, 1H), 2.89 (s, 1H), 2.57(br. s., 3H), 2.00-2.08 (m, 1H), 1.91-1.98 (m, 2H), 1.28 (d, J=17.3 Hz,1H), 1.21 (br. s., 2H), 1.01 (dd, J=7.6, 3.2 Hz, 2H), 0.61 (br. s., 1H),0.54 (br. s., 1H), 0.30-0.50 (m, 2H).

LC-MS: m/z 458.6 (M+H)⁺

Compound 726(R)-2-cyclopropyl-6-(3-isopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.64 (d, J=5.0 Hz, 1H), 7.58-7.66 (m, 1H), 7.37(s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H),6.21-6.33 (m, 1H), 5.50-5.60 (m, 1H), 4.54-4.71 (m, 1H), 4.33-4.49 (m,1.5H), 4.02-4.22 (m, 2H), 3.87 (d, J=13.8 Hz, 0.5H), 3.33-3.50 (m, 4H),3.03-3.23 (m, 2.5H), 2.21 (d, J=7.6 Hz, 0.5H), 1.96-2.16 (m, 2H),1.11-1.24 (m, 2H), 0.94-1.11 (m, 5H), 0.84-0.92 (m, 3H).

LC-MS: m/z 446.1 (M+H)⁺

Compound 721(R)-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.66 (d, J=5.0 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H),7.40 (s, 1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H), 6.89 (dd, J=17.5, 10.7 Hz,1H), 6.23-6.35 (m, 1H), 5.55-5.63 (m, 1H), 4.58-4.74 (m, 1.5H),4.38-4.50 (m, 1.5H), 3.87-4.00 (m, 2H), 3.78 (d, J=13.8 Hz, 1H),3.39-3.55 (m, 1H), 3.05-3.24 (m, 2H), 2.56-2.66 (m, 2H), 2.20-2.30 (m,1H), 1.98-2.06 (m, 2H), 1.25-1.33 (m, 6H), 0.84-0.95 (m, 4H)

LC-MS: m/z 446.1 (M+H)⁺

Compound 719(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

Step1(R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

To a solution of 4,6-dichloropyrimidin-2-amine (270 mg, 0.58 mmol) in amixture of dimethoxyethane (5 mL) and a 2M aqueous sodium carbonatesolution (0.8 mL) were added(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(100 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg,0.1 eq) under nitrogen atmosphere, and the mixture was heated for 2hours at 100° C. After cooling to ambient temperature, the separatedorganic layer was evaporated under reduced pressure. The residue wastaken up into ethyl acetate, washed in turn with a 10% aqueous potassiumcarbonate solution and brine, and dried over sodium sulfate. Afterevaporation, the residue was chromatographed on silica gel eluding with5%-20% ethyl acetate in petroleum ether to give(R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile(140 mg crude).

LC-MS: m/z 468.2 (M+H)⁺

Step 2: Compound 719(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

A mixture of above(R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile(60 mg, 0.13 mmol), potassium vinylfluoborate (25 mg, 0.2 mmol),Pd(PPh₃)₄ (3 mg, 0.1 eq), and CsF (40 mg, 0.26 mmol) were suspended in 5mL of dioxane and 1 mL of water, the resulting mixture was refluxed for1 h. After the reaction was complete, the reaction mixture wasconcentrated in vacuo, and the residue was purified by columnchromatography to afford 40 mg of title compound as yellow solid. (70%yield)

LC-MS: m/z 460.2 (M+H)⁺

¹H NMR (CHLOROFORM-d) δ: 7.92 (s, 1H), 6.87 (s, 1H), 6.65 (dd, J=17.3,10.6 Hz, 1H), 6.39 (d, J=17.5 Hz, 1H), 5.69 (d, J=10.7 Hz, 1H), 5.44(br. s., 2H), 4.61 (d, J=13.2 Hz, 1H), 4.48 (d, J=12.1 Hz, 1H), 4.07 (d,J=7.5 Hz, 1H), 3.87-3.98 (m, 2H), 3.63-3.84 (m, 2H), 3.17-3.31 (m, 2H),3.00-3.17 (m, 1H), 2.50-2.66 (m, 2H), 2.30-2.45 (m, 1H), 1.17-1.28 (m,3H), 0.97-1.13 (m, 2H), 0.61 (br. s., 1H), 0.54 (br. s., 1H), 0.46 (br.s., 2H).

LC-MS: m/z 460.2 (M+H)⁺

Compound 663(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(6-vinylpyrimidin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ:9.19-9.32 (m, 1H), 8.01 (s, 1H), 7.46-7.59 (m,1H), 6.82 (dd, J=17.3, 10.8 Hz, 1H), 6.51-6.63 (m, 1H), 5.80 (d, J=11.3Hz, 1H), 5.32 (s, 1H), 4.66 (d, J=13.1 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H),4.08 (d, J=9.8 Hz, 1H), 3.88-3.97 (m, 2H), 3.67-3.82 (m, 2H), 3.32 (br.s., 1H), 3.20-3.29 (m, 2H), 3.02-3.20 (m, 2H), 2.49-2.66 (m, 2H),2.34-2.45 (m, 1H), 1.22-1.29 (m, 3H), 1.02-1.10 (m, 2H), 0.63 (d, J=7.8Hz, 1H), 0.55 (br. s., 1H), 0.47 (br. s., 2H).

LC-MS: m/z 445.2 (M+H)⁺

Compound 701(R)-5-(2-amino-6-(2-aminoethyl)pyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.97-8.12 (m, 1H), 7.51 (br. s., 1H), 6.21 (br.s., 2H), 4.71 (d, J=12.8 Hz, 1H), 4.57 (d, J=11.0 Hz, 1H), 4.06 (s, 1H),3.52 (br. s., 3H), 3.31 (br. s., 3H), 3.22 (br. s., 2H), 2.38 (br. s.,1H), 1.71 (br. s., 1H), 1.19-1.28 (m, 3H), 0.96-1.14 (m, 4H), 0.75-0.87(m, 2H), 0.62 (br. s., 1H), 0.51 (br. s., 2H), 0.38-0.48 (m, 1H).

LC-MS: m/z 473.3 (M+H)⁺

Compound 759(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 7.95 (s, 1H), 6.88 (s, 1H), 6.66 (dd, J=17.5,10.7 Hz, 1H), 6.47 (d, J=17.6 Hz, 1H), 5.71 (d, J=11.2 Hz, 1H), 5.27(br. s., 2H), 4.64 (d, J=13.2 Hz, 2H), 4.50 (d, J=12.6 Hz, 2H), 4.16(br. s., 3H), 4.01 (br. s., 1H), 3.90 (br. s., 1H), 3.65 (d, J=17.0 Hz,1H), 3.46 (s, 3H), 3.18-3.32 (m, 2H), 3.02-3.18 (m, 1H), 2.32-2.47 (m,1H), 1.18-1.32 (m, 3H), 1.00-1.11 (m, 2H), 0.63 (br. s., 2H), 0.46 (br.s., 2H)

LC-MS: m/z 460.2 (M+H)⁺

Compound 727(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 7.51 (br. s., 1H), 6.66 (dd, J=16.7, 10.6 Hz,1H), 6.35 (d, J=16.7 Hz, 1H), 5.88 (br. s., 1H), 5.66-5.83 (m, 1H), 4.44(d, J=12.6 Hz, 1H), 4.25-4.38 (m, 2H), 4.19 (br. s., 1H), 3.98-4.10 (m,1H), 3.91 (br. s., 2H), 3.84 (br. s., 1H), 3.60-3.79 (m, 3H), 3.08-3.25(m, 2H), 2.89-3.08 (m, 1H), 2.47-2.65 (m, 2H), 2.40 (br. s., 2H),2.01-2.08 (m, 1H), 1.27 (br. s., 1H), 1.14 (br. s., 2H), 0.98-1.10 (m,2H), 0.62 (br. s., 1H), 0.53 (br. s., 1H), 6.34-0.50 (m, 2H).

LC-MS: m/z 476.6 (M+H)⁺

Compound 728(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 7.44-7.56 (m, 1H), 6.49-6.74 (m, 1H), 6.35 (d,J=16.7 Hz, 1H), 5.88 (br. s., 1H), 5.67-5.82 (m, 1H), 4.46 (d, J=12.9Hz, 1H), 4.25-4.39 (m, 2H), 4.07-4.23 (m, 3H), 3.98 (d, J=8.5 Hz, 1H),3.84 (t, J=5.1 Hz, 1H), 3.73 (t, J=5.4 Hz, 1H), 3.45 (s, 3H), 3.10-3.21(m, 1H), 3.02 (t, J=11.9 Hz, 1H), 2.39 (br. s., 2H), 2.00-2.16 (m, 1H),1.69 (br. s., 1H), 1.30-1.37 (m, 1H), 1.14 (br. s., 2H), 0.97-1.09 (m,2H), 0.64 (br. s., 1H), 0.51 (br. s., 1H), 0.45 (br. s., 1H).

LC-MS: m/z 476.6 (M+H)⁺

Compound 680(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 6.65 (d, J=10.0 Hz, 1H), 6.36 (d, J=16.8 Hz,1H), 5.65-5.84 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H),4.25-4.38 (m, 0.5H), 4.01-4.25 (m, 4H), 3.87-4.01 (m, 1H), 3.67-3.86 (m,4H), 3.39 (s, 3H), 3.09-3.22 (m, 1H), 2.95-3.09 (m, 1H), 2.54-2.71 (m,2H), 2.36-2.48 (m, 5H), 2.03 (br. s., 1H), 1.20-1.35 (m, 4H), 0.84-1.08(m, 4H).

LC-MS: m/z 478.6 (M+H)⁺

Compound 745(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 6.67 (dd, J=16.3, 10.4 Hz, 1H), 6.36 (d, J=16.1Hz, 1H), 5.65-5.85 (m, 2H), 4.13-4.34 (m, 3H), 4.03-4.11 (m, 1H), 3.95(d, J=18.8 Hz, 1H), 3.78-3.89 (m, 1H), 3.62-3.78 (m, 4H), 3.38 (s, 3H),3.27 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 1H), 2.36-2.47 (m,5H), 1.96-2.08 (m, 1H), 1.23-1.39 (m, 3H), 0.81-1.07 (m, 4H), 0.60 (br.s., 1H), 0.52 (br. s., 1H), 0.43 (br. s., 2H).

LC-MS: m/z 504.6 (M+H)⁺

Compound 755(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 6.67 (dd, J=16.7, 10.9 Hz, 1H), 6.36 (d, J=16.7Hz, 1H), 5.64-5.85 (m, 1H), 4.10-4.38 (m, 3H), 4.04 (br. s., 1H), 3.98(br. s., 1H), 3.91 (br. s., 2H), 3.61-3.83 (m, 3H), 3.04-3.34 (m, 2H),2.59 (br. s., 1H), 2.52 (d, J=10.3 Hz, 1H), 2.37-2.48 (m, 5H), 2.06 (br.s., 1H), 1.34-1.50 (m, 1H), 1.16 (br. s., 1H), 0.93-1.10 (m, 3H), 0.62(br. s., 1H), 0.27-0.56 (m, 3H)

LC-MS: m/z 490.6 (M+H)⁺

Compound 762(R)-1′-acryloyl-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-methyl-1′,2′,5′,6′-tetrahydro-[3,3′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 6.36 (d, J=16.7 Hz, 1H), 5.68-5.98 (m, 2H),4.33 (d, J=11.7 Hz, 1H), 4.22 (d, J=13.2 Hz, 2H), 4.04 (br. s., 1H),3.92 (t, J=5.0 Hz, 3H), 3.64-3.78 (m, 2H), 3.47 (d, J=7.9 Hz, 1H),2.96-3.09 (m, 2H), 2.52-2.65 (m, 2H), 2.38-2.48 (m, 5H), 2.04 (br. s.,2H), 0.95-1.07 (m, 6H), 0.83-0.95 (m, 4H)

LC-MS: m/z 492.6 (M+H)⁺

Compound 6492-cyclopropyl-6-((3R)-3-methyl-4-(2-(oxetan-2-yl)acetyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.60 (m, 1H), 7.64 (s, 1H), 7.37 (s, 1H),7.19-7.27 (m, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz,1H), 5.57 (d, J=11.0 Hz, 1H), 5.17-5.42 (m, 1H), 4.89 (m, 0.5H), 4.73(q, J=7.0 Hz, 1H), 4.46-4.62 (m, 1.5H), 4.34 (m, 2H), 4.28 (d, J=13.3Hz, 0.5H), 3.85 (t, J=13.3 Hz, 0.5H), 3.50-3.67 (m, 0.5H), 3.21-3.32 (m,1H), 2.99-3.20 (m, 1.5H), 2.76-2.94 (m, 3H), 2.46-2.60 (m, 1H),1.87-2.09 (m, 1H), 1.24-1.32 (m, 3H), 1.14-1.23 (m, 2H), 0.93-1.10 (m,3H).

LC-MS: m/z 444.0 (M+H)⁺

Compound 6482-cyclopropyl-6-((R)-3-methyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.65 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.38 (s,1H), 7.13-7.27 (m, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.13-6.40 (m,1H), 5.56 (d, J=11.5 Hz, 1H), 5.18-5.34 (m, 1H), 4.81-5.03 (m, 0.5H),4.65-4.79 (m, 1H), 4.48-4.65 (m, 1.5H), 4.30-4.42 (m, 2H), 4.26 (d,J=12.8 Hz, 0.5H), 3.86 (d, J=13.3 Hz, 0.5H), 3.49-3.66 (m, 0.5H),3.23-3.40 (m, 1H), 3.01-3.20 (m, 1.5H), 2.71-3.01 (m, 3H), 2.37-2.64 (m,1H), 1.90-2.10 (m, 1H), 1.24-1.34 (m, 3H), 1.13-1.24 (m, 2H), 0.93-1.09(m, 2H)

LC-MS: m/z 444.0 (M+H)⁺

Compound 654(R)-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.70 (d, J=4.8 Hz, 1H), 7.23 (s, 1H), 7.07 (d,J=4.8 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.30 (d, J=17.3 Hz, 1H),5.58 (d, J=11.3 Hz, 1H), 4.90 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H),4.07-4.26 (m, 2.5H), 3.93 (br. s., 2H), 3.66-3.79 (m, 0.5H), 3.58 (t,J=11.0 Hz, 0.5H), 3.46 (br. s., 1H), 3.13-3.29 (m, 1.5H), 2.95-3.13 (m,1H), 2.47-2.75 (m, 2H), 2.22 (s, 3H), 1.74 (br. s., 1H), 1.50-1.63 (m,1H), 1.37-1.46 (m, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H), 1.01-1.14 (m, 2H),0.79-0.95 (m, 2H).

LC-MS: m/z 431.5 (M+H)⁺

Compound 655(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 7.94-8.05 (m, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.60(d, J=3.5 Hz, 1H), 7.43-7.48 (m, 1H), 7.14 (dd, J=17.6, 10.8 Hz, 1H),6.55 (dd, J=17.6, 1.8 Hz, 1H), 5.81 (d, J=11.0 Hz, 1H), 4.60 (d, J=13.1Hz, 1.5H), 4.48 (d, J=13.1 Hz, 1H), 4.13 (d, J=6.0 Hz, 0.5H), 3.86-3.99(m, 2H), 3.82 (br. s., 1.5H), 3.28 (br. s., 1.5H), 3.15 (dd, J=15.7, 8.2Hz, 2H), 2.56-2.68 (m, 2H), 1.13-1.23 (m, 2H), 0.80-0.97 (m, 3H), 0.68(br. s., 1H), 0.59 (br. s., 1H), 0.51 (br. s., 2H).

LC-MS: m/z 495.1 (M+H)⁺

Compound 650(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ9.20 (d, J=11.0 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H),7.96-8.04 (m, 1H), 7.68 (dd, J=4.4, 2.9 Hz, 1H), 7.49-7.59 (m, 1H),7.06-7.23 (m, 1H), 6.86 (d, J=17.1 Hz, 1H), 5.94 (d, J=10.5 Hz, 1H),4.62-4.80 (m, 1.5H), 4.43-4.54 (m, 1.5H), 3.87-4.03 (m, 2H), 3.73-3.86(m, 1H), 2.91-3.31 (m, 3H), 2.54-2.67 (m, 2H), 2.09-2.25 (m, 1H), 1.54(td, J=8.0, 4.1 Hz, 1H), 1.11 (dd, J=13.7, 6.4 Hz, 4H), 0.79-0.94 (m,6H).

LC-MS: m/z 497.3 (M+H)⁺

Compound 652(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ9.17 (d, J=3.3 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H),7.97 (dd, J=8.4, 7.2 Hz, 1H), 7.68 (s, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.08(dd, J=17.3, 10.5 Hz, 1H), 6.74-6.90 (m, 1H), 5.89 (dd, J=10.5, 1.5 Hz,1H), 4.93 (br. s., 0.5H), 4.57 (d, J=12.5 Hz, 0.5H), 4.28-4.47 (m, 2H),4.21 (br. s., 0.5H), 3.94 (s, 2H), 3.71-3.84 (m, 0.5H), 3.50-3.68 (m,0.5H), 3.29-3.44 (m, 1H), 3.06-3.26 (m, 2H), 2.49-2.78 (m, 2H),1.50-1.62 (m, 1H), 1.45 (t, J=7.2 Hz, 1H), 1.35 (t, J=6.4 Hz, 2H),1.14-1.22 (m, 2H), 0.83-0.98 (m, 2H)

LC-MS: m/z 469.2 (M+H)⁺

Compound 651(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.08 (d, J=8.3 Hz, 1H), 7.97 (td, J=7.8, 1.3Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.47-7.56 (m, 1H), 7.09 (dd, J=17.1,10.5 Hz, 1H), 6.82 (d, J=17.1 Hz, 1H), 5.90 (dd, J=10.7, 1.6 Hz, 1H),4.61 (dd, J=13.1, 7.3 Hz, 1H), 4.41-4.55 (m, 1H), 4.12 (d, J=6.5 Hz,1H), 3.94 (s, 2H), 3.67-3.82 (m, 1H), 3.10-3.40 (m, 3H), 2.49-2.68 (m,2H), 1.56 (td, J=8.1, 4.1 Hz, 1H), 1.32-1.41 (m, 1H), 1.14-1.24 (m, 2H),0.84-0.95 (m, 2H), 0.51-0.69 (m, 4H)

LC-MS: m/z 495.2 (M+H)⁺

Compound 657(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylquinoxalin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.00 (s, 1H), 8.08-8.18 (m, 1H), 7.79-7.90 (m,1H), 7.65-7.76 (m, 2H), 7.07 (dd, J=17.8, 11.0 Hz, 1H), 6.51 (d, J=17.6Hz, 1H), 5.84 (d, J=11.0 Hz, 1H), 4.51 (d, J=13.1 Hz, 1H), 4.40 (d,J=12.8 Hz, 1H), 4.13 (q, J=7.0 Hz, 1.5H), 3.86-3.99 (m, 2.5H), 3.76 (d,J=19.8 Hz, 2H), 3.37 (d, J=7.8 Hz, 1H), 3.22-3.33 (m, 1H), 3.17 (d,J=12.3 Hz, 1H), 3.09 (br. s., 1H), 2.55-2.69 (m, 2H), 1.58-1.69 (m, 1H),1.17-1.37 (m, 3H), 1.08 (br. s., 2H), 0.83 (br. s., 2H), 0.66 (br. s.,1H), 0.55 (br. s., 1H), 0.48 (d, J=5.8 Hz, 3H).

LC-MS: m/z 495.1 (M+H)⁺

Compound 740(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(6-vinyl-1H-pyrrolo[2,3-b]pyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 10.15 (br. s., 1H), 7.69-7.87 (m, 1H),7.36-7.45 (m, 1H), 7.23 (s, 1H), 6.97 (dd, J=17.3, 11.2 Hz, 1H), 6.43(d, J=3.2 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H),4.58 (d, J=12.9 Hz, 1H), 4.45 (d, J=12.6 Hz, 1H), 4.12 (d, J=8.5 Hz,1H), 3.94 (br. s., 2H), 3.63-3.87 (m, 2H), 3.13-3.27 (m, 2H), 2.54-2.69(m, 2H), 1.95-2.02 (m, 1H), 1.54-1.74 (m, 1H), 1.22 (br. s., 2H), 0.97(dd, J=7.6, 3.5 Hz, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.50 (br.s., 2H)

LC-MS: m/z 483.6 (M+H)⁺

Compound 735(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-5-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ9.53 (s, 1H), 8.54 (d, J=3.2 Hz, 1H), 7.88-8.00(m, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.09 (dd, J=17.8, 11.0Hz, 1H), 6.41 (d, J=17.6 Hz, 1H), 5.81 (d, J=11.2 Hz, 1H), 4.59 (d,J=13.2 Hz, 1H), 4.47 (d, J=12.6 Hz, 1H), 4.1-4.2 (m, 0.5H), 3.93 (br.s., 2H), 3.82 (m, 1.5H), 3.44 (m, 1H), 3.05-3.35 (m, 3H), 2.54-2.70 (m,2H), 1.47-1.64 (m, 2H), 1.13-1.23 (m, 2H), 0.90-0.96 (m, 2H), 0.68 (br.s., 1H), 0.58 (br. s., 1H), 0.51 (br. s., 2H)

LC-MS: m/z 495.2 (M+H)⁺

Compound 744(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(1-methyl-6-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ7.90 (s, 1H), 7.77 (s, 1H), 7.21 (s, 1H), 6.99(dd, J=17.5, 10.7 Hz, 1H), 6.41 (d, J=17.3 Hz, 1H), 5.58-5.73 (m, 1H),4.60 (d, J=13.2 Hz, 1H), 4.48 (d, J=12.6 Hz, 1H), 4.20 (s, 3H), 4.11 (d,J=8.8 Hz, 1H), 3.93 (br. s., 2H), 3.65-3.85 (m, 1H), 3.44 (br. s., 1H),3.18-3.36 (m, 2H), 3.13 (d, J=10.0 Hz, 1H), 2.46-2.70 (m, 2H), 1.88-2.01(m, 1H), 1.31-1.42 (m, 1H), 1.24 (dt, J=7.0, 3.5 Hz, 2H), 0.93-1.04 (m,2H), 0.66 (br. s., 1H), 0.57 (br. s., 1H), 0.32-0.53 (m, 2H)

LC-MS: m/z 498.2 (M+H)⁺

Compound 670(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylquinazolin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.09 (d, J=8.3 Hz, 1H), 7.86-7.97 (m, 2H), 7.82(d, J=8.0 Hz, 1H), 7.58 (td, J=7.7, 1.0 Hz, 1H), 7.09 (dd, J=17.2, 10.4Hz, 1H), 6.82 (dd, J=17.3, 1.8 Hz, 1H), 5.76-5.93 (m, 1H), 4.65 (d,J=13.1 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 4.11 (d, J=9.3 Hz, 0.5H), 3.93(br. s., 2H), 3.7-3.85 (m, 1.5H), 3.48 (br. s., 1H), 3.26 (d, J=13.1 Hz,2H), 3.17 (m, 1H), 2.52-2.68 (m, 2H), 1.88 (br. s., 1H), 1.66-1.80 (m,1H), 0.81-0.99 (m, 4H), 0.62-0.79 (m, 1H), 0.57 (br. s., 1H), 0.50 (d,J=5.8 Hz, 2H)

LC-MS: m/z 495.2 (M+H)⁺

Compound 669(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinylquinazolin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ8.08 (d, J=8.5 Hz, 1H), 7.87-7.97 (m, 2H), 7.83(d, J=8.3 Hz, 1H), 7.54-7.66 (m, 1H), 7.08 (dd, J=17.2, 10.4 Hz, 1H),6.74-6.90 (m, 1H), 5.78-5.94 (m, 1H), 4.66 (d, J=11.3 Hz, 1H), 4.46-4.62(m, 1H), 4.15-4.35 (m, 1H), 3.53-3.77 (m, 1H), 3.48 (d, J=4.5 Hz, 1H),3.30 (m, 1H), 3.19 (m, 1H), 1.60-1.83 (m, 2H), 1.43 (br. s., 1H),1.16-1.29 (m, 2H), 1.04 (d, J=18.8 Hz, 2H), 0.77-0.97 (m, 4H), 0.59-0.77(m, 1H), 0.37-0.59 (m, 3H)

LC-MS: m/z 491.2 (M+H)⁺

Compound 720(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylquinolin-7-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.15-8.23 (m, 1H), 8.08-8.15 (m, 1H), 7.88 (d,J=8.3 Hz, 1H), 7.72-7.79 (m, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.56 (dd,J=8.1, 1.6 Hz, 1H), 7.07 (dd, J=17.6, 10.9 Hz, 1H), 6.34 (d, J=17.7 Hz,1H), 5.73 (d, J=11.0 Hz, 1H), 4.69 (d, J=9.4 Hz, 0.5H), 4.54 (d, J=13.2Hz, 1H), 4.42 (d, J=12.6 Hz, 1H), 4.10 (d, J=8.3 Hz, 0.5H), 3.93 (br.s., 2H), 3.69-3.86 (m, 1H), 3.16-3.36 (m, 2H), 2.99-3.16 (m, 1H),2.48-2.69 (m, 2H), 2.11-2.20 (m, 1H), 1.16-1.31 (m, 3H), 0.93-1.05 (m,2H), 0.66 (br. s., 1H), 0.56 (br. s., 1H), 0.39-0.52 (m, 2H)

LC-MS: m/z 494.9 (M+H)⁺

Compound 709(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinylquinolin-7-yl)nicotinonitrile(Exemplified by procedure COMPOUND 720)

¹H NMR (CHLOROFORM-d) δ: 8.17 (d, J=8.5 Hz, 1H), 8.11 (s, 1H), 7.86 (d,J=8.3 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.3,1.5 Hz, 1H), 7.06 (dd, J=17.7, 10.9 Hz, 1H), 6.33 (d, J=17.8 Hz, 1H),5.71 (d, J=10.8 Hz, 1H), 4.56 (d, J=12.8 Hz, 1H), 4.43 (d, J=12.3 Hz,1H), 4.09 (m, 1H), 3.72 (m, 1H), 3.29 (br. s., 2H), 3.12 (br. s., 1H),2.10-2.20 (m, 1H), 1.73 (br. s., 1H), 1.44 (br. s., 1H), 1.18-1.25 (m,2H), 1.06 (t, J=4.4 Hz, 1H), 0.94-1.04 (m, 3H), 0.81 (dd, J=7.8, 2.3 Hz,2H), 0.67 (br. s., 1H), 0.41-0.58 (m, 3H).

LC-MS: m/z 490.9 (M+H)⁺

Compound 7466-cyclopropyl-2-((R)-3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methyl-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.58 (br. s., 1H), 8.57 (br. s., 1H), 7.67 (d,J=7.3 Hz, 1H), 7.21-7.34 (m, 2H), 7.10 (dd, J=17.6, 10.9 Hz, 1H), 6.42(dd, J=17.6, 2.6 Hz, 1H), 5.82 (d, J=10.9 Hz, 1H), 4.38-4.49 (m, 1H),4.34 (d, J=12.6 Hz, 1H), 4.14 (d, J=7.0 Hz, 1H), 3.89 (br. s., 1H),3.69-3.82 (m, 2H), 3.40 (s, 3H), 3.23 (d, J=13.8 Hz, 2H), 3.02-3.17 (m,1H), 2.72 (br. s., 1H), 2.67 (br. s., 1H), 2.11 (d, J=1.8 Hz, 3H), 1.45(br. s., 1H), 1.06-1.18 (m, 2H), 0.79-0.90 (m, 1H), 0.69-0.79 (m, 2H),0.64 (br. s., 1H), 0.57 (br. s., 1H), 0.41-0.55 (m, 2H).

LC-MS: m/z 522.3 (M+H)⁺

Compound 741(R)-6-cyclopropyl-2-(3-isopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.58 (s, 1H), 8.60 (br. s., 1H), 7.79 (d,J=10.9 Hz, 1H), 7.63-7.71 (m, 1H), 7.50-7.63 (m, 1H), 7.12 (dd, J=17.6,10.9 Hz, 1H), 6.47 (d, J=17.6 Hz, 1H), 5.83-5.94 (m, 1H), 4.63-4.80 (m,1.5H), 4.37-4.58 (m, 2H), 4.04-4.26 (m, 2H), 3.93 (d, J=13.5 Hz, 1H),3.10-3.33 (m, 2H), 2.09-2.30 (m, 0.5H), 1.92-2.08 (m, 1H), 1.11 (dd,J=16.3, 6.6 Hz, 4H), 0.85-0.98 (m, 6H).

LC-MS: m/z 496.3 (M+H)⁺

Compound 717(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.56 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 7.72 (d,J=3.2 Hz, 1H), 7.68 (s, 1H), 7.45 (dd, J=9.5, 5.7 Hz, 1H), 7.10 (dd,J=17.8, 11.0 Hz, 1H), 6.42 (dd, J=17.6, 2.1 Hz, 1H), 5.72-5.90 (m, 1H),4.63 (d, J=13.2 Hz, 1H), 4.45-4.55 (m, 1H), 4.18 (br. s., 2H), 4.06 (br.s., 1H), 3.96 (br. s., 1H), 3.60-3.85 (m, 1H), 3.44-3.49 (m, 3H),3.23-3.34 (m, 1H), 3.16 (br. s., 1H), 1.97 (br. s., 1H), 1.48-1.56 (m,1H), 1.22 (dd, J=7.9, 3.8 Hz, 2H), 0.86-0.94 (m, 2H), 0.70 (br. s., 1H),0.57 (br. s., 1.5H), 0.51 (br. s., 1.5H).

LC-MS: m/z 494.6 (M+H)⁺

Compound 689(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.58 (br. s., 1H), 8.61 (br. s., 1H), 7.77 (d,J=3.0 Hz, 1H), 7.64-7.73 (m, 1H), 7.54 (br. s., 1H), 7.12 (dd, J=17.6,10.8 Hz, 1H), 6.45 (dd, J=17.7, 2.1 Hz, 1H), 5.85 (d, J=11.0 Hz, 1H),4.64 (d, J=10.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.25 (br. s., 1H),3.69-3.81 (br. s., 1H), 3.38 (d, J=15.3 Hz, 1.5H), 3.21 (br. s., 1.5H),1.75 (br. s., 1H), 1.50 (br. s., 1H), 1.26-1.37 (m, 1H), 1.23 (br. s.,2H), 0.99-1.14 (m, 2H), 0.87-0.96 (m, 2H), 0.84 (dd, J=7.8, 2.3 Hz, 2H),0.71 (br. s., 1H), 0.52-0.62 (m, 2H), 0.43-0.52 (m, 1H).

LC-MS: m/z 490.6 (M+H)⁺

Compound 688(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.59 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 7.80 (d,J=2.8 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.54-7.63 (m, 1H), 7.12 (dd,J=17.6, 10.8 Hz, 1H), 6.48 (dd, J=17.7, 2.1 Hz, 1H), 5.88 (d, J=11.0 Hz,1H), 4.63 (d, J=12.5 Hz, 1H), 4.52 (d, J=7.5 Hz, 1H), 4.13 (d, J=9.3 Hz,1H), 3.87-3.99 (m, 2H), 3.67-3.87 (m, 1H), 3.30 (br. s., 2H), 3.18 (br.s., 1H), 2.57-2.68 (m, 2H), 1.43-1.54 (m, 1H), 1.32-1.41 (m, 1H),1.19-1.26 (m, 2H), 0.87-0.97 (m, 2H), 0.67 (br. s., 1H), 0.60 (br. s.,1H), 0.40-0.55 (m, 2H).

LC-MS: m/z 494.6 (M+H)⁺

Compound 658(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.57 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 7.76 (d,J=3.5 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.49-7.60 (m, 1H), 7.11 (dd,J=17.6, 11.0 Hz, 1H), 6.45 (dd, J=17.6, 1.8 Hz, 1H), 5.85 (d, J=11.3 Hz,1H), 4.55-4.68 (m, 1H), 4.50 (dd, J=12.8, 2.3 Hz, 1H), 4.15 (br. s.,0.5H), 3.92 (br. s., 0.5H), 3.66-3.84 (m, 3H), 3.40 (s, 3H), 3.30 (br.s., 1H), 3.22 (br. s., 1H), 3.15 (d, J=7.5 Hz, 1H), 2.66 (br. s., 1H),2.56 (br. s., 1H), 1.46-1.54 (m, 1H), 1.32 (d, J=16.1 Hz, 1H), 1.19-1.24(m, 2H), 0.84-0.99 (m, 2H), 0.66 (br. s., 1H), 0.60 (br. s., 1H), 0.49(br. s., 2H).

LC-MS: m/z 508.6 (M+H)⁺

Compound 681(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.55 (s, 1H), 8.59 (dd, J=5.3, 3.0 Hz, 1H),7.73 (d, J=11.5 Hz, 1H), 7.67 (dd, J=4.5, 2.8 Hz, 1H), 7.45 (dd, J=12.5,5.5 Hz, 1H), 7.10 (ddd, J=17.6, 10.9, 1.1 Hz, 1H), 6.42 (d, J=17.6 Hz,1H), 5.82 (d, J=10.8 Hz, 1H), 4.61-4.79 (m, 1H), 4.41-4.60 (m, 2H),3.86-4.01 (m, 2H), 3.82 (d, J=13.6 Hz, 0.5H), 3.53-3.60 (m, 0.5H),3.10-3.30 (m, 2H), 3.01 (d, J=12.8 Hz, 0.5H), 2.73-2.84 (m, 0.5H),2.56-2.68 (m, 2H), 2.09-2.37 (m, 1H), 1.47-1.55 (m, 1H), 1.05-1.17 (m,4H), 0.80-1.01 (m, 6H).

LC-MS: m/z 496.6 (M+H)⁺

Compound 710(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1-vinylisoquinolin-7-yl)nicotinonitrile

1H NMR (CHLOROFORM-d) δ 8.61 (d, J=5.8 Hz, 1H), 8.30 (s, 1H), 7.95 (d,J=8.3 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.65-7.72 (m, 1H),7.58-7.65 (m, 1H), 6.64 (d, J=16.1 Hz, 1H), 5.84 (d, J=10.3 Hz, 1H),4.58 (d, J=11.5 Hz, 1H), 4.46 (d, J=11.8 Hz, 1H), 4.01-4.31 (m, 1H),3.61-3.89 (m, 1H), 3.33 (d, J=17.3 Hz, 1.5H), 3.15 (br. s., 1.5H),2.02-2.09 (m, 1H), 1.42-1.47 (m, 1H), 1.34 (d, J=8.5 Hz, 1H), 1.25-1.30(m, 3H), 1.06-1.11 (m, 1H), 0.98-1.02 (m, 2H), 0.90 (t, J=6.7 Hz, 1H),0.80-0.84 (m, 2H), 0.68 (br. s., 1H), 0.52-0.56 (m, 1H), 0.46-0.49 (m,1H)

LC-MS: m/z 492.0 (M+H)⁺

Compound 685(R)-5-((2-chloropyridin-4-yl)methyl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.33 (d, J=5.0 Hz, 1H), 7.49 (s, 1H), 7.12 (s,1H), 6.98-7.06 (m, 1H), 4.47 (d, J=12.5 Hz, 1H), 4.30-4.50 (m, 2.5H),4.20-4.30 (m, 1H), 4.04 (s, 1H), 3.60-3.90 (s, 1H), 2.90-3.45 (m, 1H),2.01 (s, 1H), 1.80-1.91 (m, 1H), 1.72 (s, 1H), 1.09-1.17 (m, 2H),0.93-1.09 (m, 4H), 0.74-0.86 (m, 2H), 0.37-0.65 (m, 4H)

LC-MS: m/z 462.2 (M+H)⁺

Compound 684(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-((2-vinylpyridin-4-yl)methyl)nicotinonitrile

¹H NMR (CHLOROFORM-d): 8.50 (d, J=5.0 Hz, 1H), 7.47 (s, 1H), 7.12 (s,1H), 6.89-6.99 (m, 1H), 6.80 (dd, J=17.6, 10.8 Hz, 1H), 6.16-6.29 (m,1H), 5.44-5.57 (m, 1H), 4.25-4.60 (m, 2.5H), 4.12-4.20 (m, 1H), 4.03 (s,2H), 3.49-3.90 (m, 1H), 2.95-3.29 (m, 2.5H), 1.85-1.98 (m, 1H), 1.71 (s,1H), 1.35-1.45 (m, 1H), 1.07-1.17 (m, 2H), 0.92-1.07 (m, 4H), 0.76-0.82(m, 2H), 0.30-0.63 (m, 4H)

LC-MS: m/z 454.2 (M+H)⁺

Compound 708(R)-5-((2-chloropyridin-4-yl)methyl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.34 (d, J=5.3 Hz, 1H), 7.49 (s, 1H), 7.11 (s,1H), 7.03 (d, J=5.0 Hz, 1H), 4.39-4.52 (m, 2H), 4.33 (d, J=12.3 Hz, 1H),4.04 (s, 2H), 3.85-3.97 (m, 2H), 3.66-3.81 (m, 1H), 3.01-3.22 (m, 3H),2.51-2.65 (m, 2H), 1.79-1.92 (m, 1H), 1.31-1.39 (m, 1H), 1.08-1.15 (m,2H), 0.93-1.03 (m, 2H), 0.46-0.63 (m, 4H)

LC-MS: m/z 466.2 (M+H)⁺

Compound 697(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-((2-vinylpyridin-4-yl)methyl)nicotinonitrile

A mixture of(R)-5-((2-chloropyridin-4-yl)methyl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile(80 mg, 0.172 mmol), potassium vinyltrifluoroborate (46 mg, 0.343 mmol),Pd(dppf)Cl₂ (7 mg, 0.009 mmol) and CsF (79 mg, 0.515 mmol) indioxane/H₂O was stirred at 100° C. for 16 hours. The mixture was dilutedwith EtOAc (30 mL) and filtered. The filtrated was partitioned betweenEtOAc (30 mL) and water (10 mL), the organic layer was washed with water(10 mL), brine and dried over Na₂SO₄ and concentrated to give the crudewhich was purified by prep-TLC to give 25 mg of the product.

¹H NMR (CHLOROFORM-d): 8.47 (d, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.10 (s,1H), 6.87-6.97 (m, 1H), 6.76 (dd, J=17.3, 10.8 Hz, 1H), 6.18 (dd,J=17.6, 1.0 Hz, 1H), 5.41-5.53 (m, 1H), 4.39 (d, J=12.8 Hz, 1H), 4.27(d, J=12.5 Hz, 1H), 4.01 (m, 2H), 3.80-3.92 (m, 2H), 3.51-3.79 (m, 2H),2.99-3.18 (m, 3H), 2.42-2.66 (m, 2H), 1.85-1.97 (m, 1H), 1.30-1.40 (m,1H), 1.03-1.12 (m, 2H), 0.88-1.00 (m, 2H), 0.30-0.59 (m, 4H)

LC-MS: m/z 458.3 (M+H)⁺

Compound 698 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((2-vinyl-1,7-naphthyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 9.48 (s, 1H), 8.59 (d, J=5.8 Hz, 1H), 7.90 (br.s., 1H), 7.68-7.77 (m, 1H), 7.35-7.48 (m, 1H), 6.91 (dd, J=17.4, 10.9Hz, 1H), 6.56 (s, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.67 (d, J=11.0 Hz, 1H),4.86-4.98 (m, 0.5H), 4.51-4.62 (d, 0.5H) 4.14-4.38 (m, 3H), 3.94 (br.s., 2H), 3.70-3.81 (m, 0.5H), 3.59 (t, J=10.8 Hz, 0.5H), 3.27-3.41 (m,1H), 3.01-3.24 (m, 2H), 2.48-2.78 (m, 2H), 1.97-2.09 (m, 1H), 1.44 (d,J=6.5 Hz, 1.5H), 1.34 (d, J=6.8 Hz, 1.5H), 1.10-1.20 (m, 2H), 0.94-1.06(m, 2H).

LC-MS: m/z 483.2 (M+H)⁺

Compound 679 (General Procedure 7)(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 6.57-6.47(m, 2H), 6.08 (s, 1H), 4.75-4.64 (m, 0.5H), 4.49 (t, J=11.8 Hz, 1H),4.37 (t, J=10.9 Hz, 1H), 4.14-4.09 (m, 0.5H), 3.89 (ddd, J=7.5, 3.5, 2.5Hz, 0.5H), 3.81-3.64 (m, 2.5H), 3.39 (s, 3H), 3.31-3.17 (m, 1.5H), 3.10(td, J=12.8, 3.4 Hz, 1H), 2.69 (ddd, J=22.8, 14.8, 9.9 Hz, 2H), 2.52(dd, J=20.7, 9.1 Hz, 0.5H), 2.06 (ddd, J=7.5, 4.5, 1.6 Hz, 1H), 1.28 (m,J=4.7 Hz, 1H), 1.15 (m, 2H), 1.08-0.99 (m, 2H), 0.72-0.52 (m, 2H),0.52-0.39 (m, 2H).

LC-MS: m/z NB250-076-2 481.1 (M+H)⁺

Compound 678 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.26 (d, J=5.7 Hz, 1H), 7.62 (s, 1H), 6.72 (dd,J=17.4, 10.8 Hz, 1H), 6.58 (s, 1H), 6.46 (d, J=4.1 Hz, 1H), 6.20 (d,J=17.4 Hz, 1H), 5.94 (s, 1H), 5.49 (d, J=10.8 Hz, 1H), 4.70 (dd, J=14.5,4.5 Hz, 0.5H), 4.46 (t, J=11.4 Hz, 1H), 4.33 (d, J=10.6 Hz, 1H),4.13-4.07 (m, 0.5H), 3.92-3.85 (m, 0.5H), 3.83-3.62 (m, 2.5H), 3.39 (s,3H), 3.31-3.16 (m, 1.5H), 3.09 (td, J=13.2, 3.7 Hz, 1H), 2.82-2.58 (m,2H), 2.58-2.45 (m, 0.5H), 2.10 (dt, J=4.5, 3.0 Hz, 1H), 1.28 (s, 1H),1.18-1.10 (m, 2H), 1.02 (ddd, J=9.9, 6.4, 3.2 Hz, 2H), 0.73-0.53 (m,2H), 0.53-0.39 (m, 2H).

LC-MS: m/z 473.2 (M+H)⁺

Compound 661 (General Procedure 7)(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.8 Hz, 1H), 7.60 (s, 1H), 6.54 (s,1H), 6.51 (dd, J=5.8, 2.0 Hz, 1H), 6.15 (s, 1H), 4.90 (s, 0.5H), 4.54(d, J=13.4 Hz, 0.5H), 4.35-4.16 (m, 2.5H), 3.93 (s, 2H), 3.74 (d, J=13.4Hz, 0.5H), 3.58 (d, J=11.0 Hz, 0.5H), 3.30 (dd, J=10.8, 6.4 Hz, 1H),3.15 (t, J=12.2 Hz, 1H), 3.08-3.01 (m, 0.5H), 2.74-2.51 (m, 2H), 2.07(ddd, J=12.6, 8.0, 4.7 Hz, 1H), 1.42 (d, J=6.6 Hz, 1.5H), 1.32 (d, J=6.7Hz, 1.5H), 1.13 (dt, J=7.2, 3.6 Hz, 2H), 1.05 (ddd, J=10.3, 6.6, 3.5 Hz,2H).

LC-MS: m/z 441.0 (M+H)⁺

Compound 677 (General Procedure 7)(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.01 (d, J=5.7 Hz, 1H), 7.59 (s, 1H), 6.49 (d,J=1.8 Hz, 1H), 6.46 (dd, J=5.7, 2.0 Hz, 1H), 6.41 (s, 1H), 4.66 (d,J=13.6 Hz, 0.5H), 4.45 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.7 Hz, 1H), 4.06(d, J=9.3 Hz, 0.5H), 3.91 (s, 2H), 3.80 (d, J=13.2 Hz, 0.5H), 3.72 (d,J=11.6 Hz, 0.5H), 3.56 (m, 0.5H), 3.27-3.01 (m, 2.5H), 2.59 (dd, J=17.2,5.2 Hz, 1.5H), 2.11-2.04 (m, 1H), 1.98 (m, 0.5H), 1.43-1.27 (m, 1H),1.18-1.09 (m, 2H), 1.07-0.98 (m, 2H), 0.63 (m, J=7.2, 4.7 Hz, 1H),0.58-0.28 (m, 3H).

LC-MS: m/z 467.0 (M+H)⁺

Compound 676 (General Procedure 6)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.20 (d, J=6.1 Hz, 1H), 7.63 (s, 1H), 6.73 (dd,J=17.5, 10.9 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 6.63 (d, J=3.1 Hz, 1H),6.29 (d, J=17.5 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.69 (d, J=11.0 Hz,0.5H), 4.46 (d, J=13.0 Hz, 1H), 4.35 (d, J=13.1 Hz, 1H), 4.10 (d, J=7.7Hz, 0.5H), 3.92 (d, J=3.9 Hz, 2H), 3.74 (ddd, J=21.2, 17.7, 8.0 Hz,1.5H), 3.30-3.17 (m, 1.5H), 3.13-3.03 (m, 1H), 2.69-2.48 (m, 2H),2.15-2.06 (m, 1H), 1.28 (d, J=5.0 Hz, 1H), 1.14 (dt, J=7.3, 3.6 Hz, 2H),1.08-0.98 (m, 2H), 0.76-0.62 (m, 1H), 0.62-0.32 (m, 3H).

LC-MS: m/z 459.0 (M+H)⁺

Compound 718 (General Procedure 7)(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.7 Hz, 1H), 7.60 (s, 1H), 6.50 (d,J=2.1 Hz, 1H), 6.46 (dd, J=5.7, 2.2 Hz, 1H), 5.79 (s, 1H), 4.43 (dd,J=52.6, 11.8 Hz, 2.5H), 4.16 (s, 2H), 4.00 (s, 1.5H), 3.67 (d, J=24.8Hz, 1H), 3.46 (s, 3H), 3.21 (dd, J=13.0, 3.4 Hz, 1H), 3.09 (t, J=11.3Hz, 1H), 2.07 (ddd, J=12.7, 8.0, 4.7 Hz, 1H), 1.38 (s, 1H), 1.15 (dt,J=7.5, 3.7 Hz, 2H), 1.08-1.00 (m, 2H), 0.67 (s, 1H), 0.63-0.39 (m, 3H).

LC-MS: m/z 467.2 (M+H)⁺

Compound 711 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.26 (d, J=5.7 Hz, 1H), 7.62 (s, 1H), 6.71 (dd,J=17.4, 10.8 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 6.45 (dd, J=5.7, 2.3 Hz,1H), 6.18 (dd, J=17.4, 1.0 Hz, 1H), 6.01 (s, 1H), 5.47 (dd, J=10.8, 0.9Hz, 1H), 4.81-4.26 (m, 2.6H), 4.16 (s, 2H), 3.95 (d, J=43.6 Hz, 1.5H),3.70 (s, 1H), 3.46 (s, 3H), 3.20 (dd, J=13.0, 3.4 Hz, 1H), 3.07 (t,J=11.4 Hz, 1H), 2.15-2.07 (m, 1H), 1.41 (s, 1H), 1.19-1.10 (m, 2H), 1.02(ddd, J=10.2, 6.6, 3.4 Hz, 2H), 0.67 (s, 1H), 0.61-0.37 (m, 3H).

LC-MS: m/z NB295-002-01 459.1 (M+H)⁺

Compound 743(R)-6-cyclopropyl-2-(3-isopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.8 Hz, 1H), 7.60 (d, J=3.1 Hz, 1H),6.72 (dd, J=17.4, 10.8 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J=4.3 Hz, 1H),6.37 (s, 1H), 6.23 (d, J=17.5 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H),4.68-4.47 (m, 1.5H), 4.37 (t, J=12.7 Hz, 1.5H), 4.28 (d, J=13.4 Hz,0.5H), 4.22-4.13 (m, 1H), 4.08 (d, J=13.5 Hz, 0.5H), 3.88 (d, J=13.6 Hz,0.5H), 3.56 (d, J=10.6 Hz, 0.5H), 3.47 (d, J=2.5 Hz, 3H), 3.42 (dd,J=13.3, 2.9 Hz, 0.5H), 3.24-2.95 (m, 2.5H), 2.19-2.04 (m, 2H), 1.28 (d,J=4.7 Hz, 1H), 1.19-1.11 (m, 1H), 1.07 (d, J=6.5 Hz, 3H), 1.05-0.97 (m,2H), 0.91 (dd, J=15.7, 6.8 Hz, 3H).

LC-MS: m/z NB295-018-01 461.4 (M+H)⁺

Compound 731(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

Step 1:(R)-tert-butyl-4-(5-(2-chloropyridin-4-ylamino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate

To a solution of (R)-tert-butyl4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(1.5 g, 3.363 mmol) and 2-chloropyridin-4-amine (518.6 mg, 4.036 mmol)in 1,4-dioxane (20 mL) was added Pd(OAc)₂ (76 mg, 0.34 mmol), BINAP(314.3 mg, 0.505 mmol) and Cs₂CO₃ (2.2 g, 6.726 mmol) at r.t. under N₂.The resulting mixture was heated and stirred at 155° C. under N₂ inmicrowave for 1 h. The solvent was removed in vacuum and the residue waspurified via column chromatography (petroleum ether: EtOAc) to affordthe title compound (1.1 g, 66.2%) as a yellow solid.

LC-MS: m/z 495.0 (M+H)⁺

Step 2: (R)-tert-butyl4-(5-((2-chloropyridin-4-yl)(methyl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate

To a solution of (R)-tert-butyl4-(5-(2-chloropyridin-4-ylamino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(550 mg, 1.1 mmol) in anhydrous THF (10 mL) was added NaH (89 mg, 2.22mmol) and iodomethane (2 drops) at r.t. The reaction mixture was stirredat r.t. for 3 hrs. The reaction mixture was quenched by water at 0° C.The mixture was extracted with EtOAc (15 mL×2). The combined organiclayer was washed with brine, dried over Na₂SO₄. The organic phase wasfiltered and the filtrate was concentrated in vacuum to give out thetitle compound (crude, 567 mg) as a yellow solid.

LC-MS: m/z 509.1 (M+H)⁺

Step 3:(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile

To a solution of (R)-tert-butyl4-(5-((2-chloropyridin-4-yl)(methyl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate(567 mg, 1.1 mmol) in anhydrous DCM (5 mL) was added TFA (5 mL) at r.t.The reaction mixture was stirred at r.t. for 2 hrs. The solvent wasremoved in vacuum and the residue was adjusted to pH>7.0. The residuemixture was extracted with EtOAc (15 mL×2). The combined organic layerwas washed with brine, dried over Na₂SO₄. The organic phase was filteredand the filtrate was concentrated in vacuum to give out the titlecompound (crude, 432 mg) as a yellow solid.

LC-MS: m/z 409.1 (M+H)⁺

Step 4:(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

To a solution of(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile(410 mg, 1.0 mmol) in DMF (8 mL) was added sodium 3-hydroxypropanoate(203.5 mg, 1.5 mmol), HATU (572.3 mg, 1.5 mmol) and DIPEA (194 mg, 1.5mmol) at r.t. The reaction mixture was stirred at r.t. for 3 hrs. Thesolvent was removed in vacuum and the residue was purified via silicagel column chromatography (DCM: MeOH) to afford the title compound (270mg, 56.3%) as a pale yellow solid.

¹H NMR (CHLOROFORM-d) δ: 8.03 (d, J=5.8 Hz, 1H), 7.56 (s, 1H), 6.45 (s,1H), 6.35 (d, J=3.5 Hz, 1H), 4.70 (d, J=11.2 Hz, 0.5H), 4.51 (d, J=13.0Hz, 1H), 4.39 (d, J=13.4 Hz, 1H), 4.10 (d, J=9.2 Hz, 0.5H), 3.93 (d,J=4.5 Hz, 2H), 3.86-3.65 (m, 1.5H), 3.40 (s, 1H), 3.30 (s, 3H),3.28-3.15 (m, 1.5H), 3.15-3.01 (m, 1H), 2.69-2.44 (m, 2H), 1.89-1.78 (m,1H), 1.28 (d, J=5.0 Hz, 1H), 1.13 (s, 2H), 1.01 (d, J=11.8 Hz, 2H),0.82-0.65 (m, 1H), 0.64-0.32 (m, 3H)

LC-MS: m/z 481.0 (M+H)⁺

Step 5: Compound 731(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(methyl(2-vinylpyridin-4-yl)amino)nicotinonitrile

To a solution of(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile(270 mg, 0.563 mmol) in isopropanol (10 mL) and H₂O (3 mL) was addedVinyltrifluoroboric acid potassium salt (113.1 mg, 0.844 mmol),Pd(dppf)Cl₂ (49.0 mg, 0.06 mmol) and DIPEA (145.3 mg, 1.126 mmol) atr.t. under N₂. The reaction mixture was heated and stirred at refluxunder N₂ overnight. The solvent was removed in vacuum and the residuewas purified via silica gel column chromatography (DCM: MeOH) to affordthe title compound (121 mg, 45.5%) as a pale yellow solid.

¹H NMR (CHLOROFORM-d) δ: 8.25 (d, J=5.9 Hz, 1H), 7.58 (s, 1H), 6.71 (dd,J=17.4, 10.7 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.20 (d, J=17.3 Hz,1H), 5.45 (d, J=11.2 Hz, 1H), 4.69 (d, J=13.4 Hz, 0.4H), 4.49 (d, J=13.0Hz, 1H), 4.37 (d, J=12.7 Hz, 1H), 4.10 (d, J=8.6 Hz, 0.6H), 3.92 (s,2H), 3.86-3.65 (m, 1.5H), 3.42 (s, 1H), 3.31 (s, 3H), 3.22 (m, 1.5H),3.15-3.00 (m, 1H), 2.69-2.45 (m, 2H), 1.88 (ddd, J=12.7, 8.1, 4.7 Hz,1H), 1.40-1.31 (m, 1H), 1.12 (s, 2H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).

LC-MS: m/z 473.4 (M+H)⁺

Compound 699(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

To a solution of(R)-5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(675 mg, 1.487 mmol) in anhydrous THF (15 mL) was added iodomethane (0.5mL) and NaH (119 mg, 2.974 mmol) at r.t. The reaction mixture wasstirred at r.t. for 3 hrs. The reaction mixture was quenched by water at0° C. The mixture was extracted with EtOAc (15 mL×2). The combinedorganic layer was washed with brine, dried over Na₂SO₄. The organicphase was filtered and the filtrate was concentrated in vacuum. Theresidue was purified via silica gel column chromatography (DCM: MeOH) toafford the title compound (350 mg, 50.3%) as a white solid.

¹H NMR (CHLOROFORM-d) δ: 8.04 (d, J=5.7 Hz, 1H), 7.54 (s, 1H), 6.42 (d,J=44.6 Hz, 2H), 4.92 (s, 0.5H), 4.55 (d, J=13.0 Hz, 0.5H), 4.40-4.25 (m,2H), 4.22 (d, J=13.9 Hz, 0.5H), 3.83 (d, J=13.7 Hz, 0.5H), 3.76 (t,J=6.3 Hz, 2H), 3.57 (t, J=11.5 Hz, 0.5H), 3.39 (s, 3H), 3.37-3.33 (m,0.5H), 3.31 (s, 3H), 3.28-2.97 (m, 2H), 2.85-2.65 (m, 1H), 2.64-2.51 (m,1H), 1.80 (ddd, J=12.5, 8.0, 4.6 Hz, 1H), 1.36 (dd, J=41.2, 6.2 Hz, 3H),1.12 (s, 2H), 1.07-0.93 (m, 2H).

LC-MS: m/z 469.2 (M+H)⁺

Compound 690 (General Procedure 6)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(methyl(2-vinylpyridin-4-yl)amino)nicotinonitrile

To a solution of(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(330 mg, 0.71 mmol) in isopropanol (30 mL) and H₂O (3 mL) was addedVinyltrifluoroboric acid potassium salt (142.1 mg, 1.06 mmol),Pd(dppf)Cl₂ (58.0 mg, 0.071 mmol) and DIPEA (182 mg, 1.41 mmol) at r.t.under N₂. The reaction mixture was heated and stirred at reflux under N₂overnight. The solvent was removed in vacuum and the residue waspurified via silica gel column chromatography (DCM: MeOH) to afford thetitle compound (89 mg, 27.5%) as a white solid.

¹H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.9 Hz, 1H), 7.55 (s, 1H), 6.71 (dd,J=17.4, 10.8 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.20 (d, J=17.3 Hz,1H), 5.46 (d, J=11.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d, J=13.1 Hz, 0.5H),4.34-4.16 (m, 2.5H), 3.89-3.68 (m, 2.5H), 3.56 (t, J=11.5 Hz, 0.5H),3.39 (s, 3H), 3.31 (s, 3H), 3.29 (s, 1H), 3.10 (m, 1.5H), 2.80-2.52 (m,2H), 1.88-1.83 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.6 Hz,1.5H), 1.10 (m, 2H), 0.97 (m, 2H).

LC-MS: m/z 461.2 (M+H)⁺

Compound 660 (General Procedure 6)(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-ylamino)picolinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.32 (d, J=5.8 Hz, 1H), 7.59 (s, 1H), 7.01 (s,1H), 6.72 (d, J=3.8 Hz, 1H), 6.62 (s, 1H), 4.92 (s, 0.5H), 4.55 (d,J=12.7 Hz, 0.5H), 4.30 (t, J=11.2 Hz, 2H), 4.22 (d, J=12.7 Hz, 0.5H),3.83 (d, J=13.8 Hz, 0.5H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (t, J=11.5 Hz,0.5H), 3.39 (s, 3H), 3.33 (d, J=12.5 Hz, 1H), 3.21-3.04 (m, 1.5H), 2.73(ddd, J=22.1, 14.2, 6.5 Hz, 1H), 2.64-2.53 (m, 1H), 2.05-1.99 (m, 1H),1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.7 Hz, 1.5H), 1.18-1.10 (m, 2H),1.09-0.98 (m, 2H).

LC-MS: m/z 446.0 (M+H)⁺

Compound 659 (General Procedure 6)(R)-4,4′-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-ylazanediyl)dipicolinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.62 (d, J=5.5 Hz, 2H), 7.53 (s, 1H), 7.28-7.20(m, 4H), 4.95 (s, 0.5H), 4.58 (d, J=10.0 Hz, 0.5H), 4.37 (dd, J=42.6,13.4 Hz, 2.5H), 3.89 (d, J=13.8 Hz, 0.5H), 3.77 (t, J=6.3 Hz, 2H),3.66-3.57 (m, 0.5H), 3.44 (s, 0.5H), 3.40 (s, 3H), 3.35-3.13 (m, 1.5H),2.87-2.67 (m, 1H), 2.62 (dd, J=13.7, 7.4 Hz, 1H), 1.68 (d, J=4.3 Hz,1H), 1.44 (d, J=6.6 Hz, 1.5H), 1.34 (d, J=6.3 Hz, 1.5H), 1.11 (dt,J=6.9, 3.5 Hz, 2H), 0.97-0.88 (m, 2H).

LC-MS: m/z 548.1 (M+H)⁺

Compound 729 (General Procedure 6)(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-ylamino)picolinamide

¹H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.7 Hz, 1H), 7.98 (s, 1H), 7.61 (s,1H), 7.53 (s, 1H), 6.62 (dd, J=5.6, 2.3 Hz, 1H), 6.03 (s, 1H), 5.65 (s,1H), 4.92 (s, 0.5H), 4.55 (d, J=13.9 Hz, 0.5H), 4.27 (t, J=11.1 Hz, 2H),4.19 (d, J=13.0 Hz, 0.5H), 3.82 (d, J=13.0 Hz, 0.5H), 3.76 (t, J=6.2 Hz,2H), 3.57 (t, J=11.5 Hz, 0.5H), 3.40 (s, 3H), 3.34-3.23 (m, 1H), 3.15(t, J=12.1 Hz, 1H), 3.10-3.00 (m, 0.5H), 2.84-2.65 (m, 1H), 2.60 (m,1H), 2.07 (ddd, J=12.6, 8.0, 4.6 Hz, 1H), 1.41 (d, J=6.2 Hz, 1.5H), 1.31(d, J=6.7 Hz, 1.5H), 1.13 (dt, J=7.4, 3.6 Hz, 2H), 1.00 (td, J=6.6, 3.4Hz, 2H).

LC-MS: m/z 464.1 (M+H)⁺

Compound 742 (General Procedure 6)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methyl-5-(2-vinylpyridin-4-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.7 Hz, 1H), 6.70 (dd, J=17.4, 10.8Hz, 1H), 6.49 (s, 1H), 6.35 (s, 1H), 6.19 (d, J=17.4 Hz, 1H), 5.79 (s,1H), 5.48 (d, J=10.9 Hz, 1H), 4.68 (d, J=12.8 Hz, 0.5H), 4.51-4.38 (m,0.5H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.08 (d, J=9.0Hz, 0.5H), 3.93 (s, 2H), 3.82-3.70 (m, 1H), 3.31 (dd, J=19.9, 7.5 Hz,0.5H), 3.24-3.12 (m, 1H), 3.11-2.97 (m, 1H), 2.56 (m, 2H), 2.39 (s, 3H),2.11 (ddd, J=12.6, 8.0, 4.7 Hz, 1H), 1.35-1.25 (m, 1H), 1.10 (s, 2H),0.97 (dd, J=7.9, 3.2 Hz, 2H), 0.78-0.34 (m, 4H).

LC-MS: m/z 473.4 (M+H)⁺

Compound 748 (General Procedure 6)5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)nicotinonitrile

To a solution of(R)-5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile(300 mg, 0.761 mmol) in DMF (3 mL) was added (R)-2-(oxetan-2-yl)aceticacid (115 mg, 0.99 mmol), HATU (436.0 mg, 1.142 mmol) and DIPEA (196.4mg, 1.53 mmol) at r.t. The reaction mixture was stirred at r.t. for 3hs. The solvent was removed in vacuum and the residue was purified viasilica gel column chromatography (DCM: MeOH) to afford the titlecompound (182 mg, 48.5%) as a pale yellow solid.

¹H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.7 Hz, 1H), 7.60 (s, 1H), 6.50 (d,J=1.8 Hz, 1H), 6.47 (dd, J=5.7, 2.0 Hz, 1H), 5.80 (s, 1H), 5.27 (dt,J=13.0, 6.5 Hz, 1H), 4.72 (dd, J=14.0, 8.0 Hz, 1H), 4.65-4.43 (m, 2H),4.37 (d, J=13.2 Hz, 1H), 4.09 (d, J=7.2 Hz, 0.5H), 3.95 (d, J=15.5 Hz,0.5H), 3.80-3.67 (m, 1H), 3.28 (ddd, J=9.8, 9.1, 5.3 Hz, 1H), 3.16 (d,J=11.2 Hz, 6.5H), 3.13-3.03 (m, 1H), 2.98 (dd, J=15.2, 6.8 Hz, 1H),2.93-2.78 (m, 2H), 2.78-2.66 (m, 0.5H), 2.66-2.47 (m, 1H), 2.10-2.02 (m,1H), 1.28 (d, J=4.9 Hz, 1H), 1.15 (dt, J=7.3, 3.5 Hz, 2H), 1.04 (dt,J=7.0, 3.2 Hz, 2H), 0.77-0.38 (m, 4H).

LC-MS: m/z 494.0 (M+H)⁺

Compound 662(R)—N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)—N-(2-vinylpyridin-4-yl)acetamide

A solution of(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylpyridin-4-ylamino)nicotinonitrile(200 mg, 0.448 mmol) in acetic anhydride (5 mL) was heated and stirredat 135° C. overnight. The solvent was removed in vacuum and the residuewas purified via reverse phase silica gel column chromatography(MeOH:H₂O) to afford the title compound (16 mg, 7.3%) as a pale yellowsolid.

¹H NMR (CHLOROFORM-d) δ: 8.52 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 7.36 (d,J=5.3 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 6.78 (dd, J=17.4, 10.8 Hz, 1H),6.23 (d, J=17.3 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H), 4.92 (s, 1H), 4.55 (d,J=11.4 Hz, 1H), 4.40-4.23 (m, 3H), 3.84 (d, J=12.8 Hz, 1H), 3.76 (t,J=6.3 Hz, 2H), 3.57 (t, J=11.0 Hz, 1H), 3.39 (s, 3H), 3.35 (s, 1H), 3.17(dt, J=24.0, 11.2 Hz, 2H), 2.73 (ddd, J=23.2, 13.8, 6.3 Hz, 1H), 2.59(dd, J=13.3, 7.2 Hz, 1H), 2.20-2.06 (m, 3H), 2.01 (dt, J=12.8, 6.2 Hz,1H), 1.40 (d, J=5.9 Hz, 2H), 1.29 (d, J=6.7 Hz, 2H), 1.16 (d, J=4.3 Hz,3H), 1.03 (d, J=7.5 Hz, 1H).

LC-MS: m/z 489.3 (M+H)⁺

Compound 758 (General Procedure 7)(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.12 (d, J=5.4 Hz, 1H), 7.82 (d, J=5.7 Hz, 1H),6.83 (d, J=5.4 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.40 (s, 2H),5.90 (d, J=17.5 Hz, 1H), 5.47 (d, J=10.9 Hz, 1H), 4.71 (d, J=12.5 Hz,0.5H), 4.45 (dd, J=16.5, 9.9 Hz, 1.5H), 4.33-4.22 (m, 1H), 3.85 (d,J=13.3 Hz, 0.5H), 3.82-3.70 (m, 2H), 3.57 (d, J=10.5 Hz, 0.5H),3.49-3.41 (m, 0.5H), 3.39 (d, J=3.3 Hz, 3H), 3.05 (dddd, J=21.0, 19.1,13.7, 2.9 Hz, 2H), 2.82-2.54 (m, 2H), 2.27 (dd, J=16.7, 6.8 Hz, 0.5H),2.18 (ddd, J=12.8, 8.2, 4.8 Hz, 1H), 1.35-1.27 (m, 1H), 1.18-0.97 (m,7H), 0.91 (d, J=6.8 Hz, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H).

LC-MS: m/z 475.6 (M+H)⁺

Compound 764 (General Procedure 7)6-cyclopropyl-2-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.10 (d, J=5.3 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H),6.82 (d, J=5.4 Hz, 1H), 6.69 (s, 1H), 6.58 (dd, J=17.6, 10.8 Hz, 1H),6.39 (s, 1H), 5.89 (d, J=17.5 Hz, 1H), 5.46 (d, J=10.9 Hz, 1H),5.32-5.24 (m, 1H), 4.83-4.61 (m, 1.5H), 4.56 (dtd, J=7.7, 5.8, 1.8 Hz,1H), 4.48 (d, J=13.5 Hz, 0.5H), 4.46-4.39 (m, 1H), 4.27 (d, J=11.9 Hz,1H), 3.88 (d, J=13.4 Hz, 0.5H), 3.56 (d, J=10.0 Hz, 0.5H), 3.45 (dd,J=13.4, 3.2 Hz, 0.5H), 3.13-2.92 (m, 3H), 2.92-2.75 (m, 2H), 2.65-2.44(m, 1H), 2.31-2.24 (m, 0.5H), 2.21-2.10 (m, 2H), 1.16-1.07 (m, 2H), 1.05(dd, J=6.5, 3.0 Hz, 3H), 1.04-0.98 (m, 2H), 0.92 (d, J=6.8 Hz, 1H), 0.86(d, J=6.8 Hz, 2H).

LC-MS: m/z 487.6 (M+H)⁺

Compound 763 (General Procedure 7)

¹H NMR (CHLOROFORM-d) δ: 8.08 (d, J=5.6 Hz, 1H), 7.81 (s, 1H), 6.87 (d,J=5.6 Hz, 1H), 6.59 (dd, J=17.5, 10.9 Hz, 1H), 6.43 (s, 1H), 5.94 (d,J=17.6 Hz, 1H), 5.53 (d, J=10.9 Hz, 1H), 5.31-5.22 (m, 1H), 4.77-4.68(m, 1H), 4.59-4.51 (m, 1H), 4.41 (s, 1H), 4.29-4.31 (m, 1 H), 4.10-4.03(m, 1H), 3.96-3.89 (m, 0.5H), 3.74-3.76 (m, 1H), 3.10-3.41 (m, 3H),2.83-2.90 (m, 2.5H), 2.54-2.55 (m, 1H), 2.18-2.20 (m, 1H), 1.35-1.36 (m,1H), 1.14-1.16 (m, 2H), 1.04-1.06 (m, 2H), 0.38-0.49 (m, 4H).

LC-MS: m/z 485.6 (M+H)⁺

Compound 756 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

To a solution of(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile(180 mg, 0.46 mmol) in 10 mL DMF was added sodium 3-hydroxypropanoate(104 mg, 0.92 mmol), and triethylamine (1 mL), HATU (350 mg, 0.92 mmol).The resulting reaction mixture was stirred at r.t. for overnight. AfterTLC showed the complete conversion of starting material to product, thereaction mixture was concentrated and purified by Prep-HPLC (50%EtOAc/petroleum ether) to get 100 mg title compound.

¹H NMR (CHLOROFORM-d) δ8.11 (d, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 6.82(dd, 1H), 6.53-6.62 (m, 1H), 6.40 (s, 1H), 5.89 (d., 1H), 5.45 (s, 1H),4.75 (m, 0.5H), 4.37-4.32 (dd, 2H), 3.92 (m, 0.5H), 3.39-3.05 (m, 3H),2.61-2.60 (m, 2H), 2.20-1.69 (m, 1H), 1.28-1.26 (m, 1H), 1.40-1.00 (m,4H), 0.47-0.45 (m, 4H).

LC-MS: m/z 4 459 (M+H)⁺

Compound 656(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-N-methoxy-N-methylbenzamide

To a solution of(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)benzoicacid (450 mg, 1 mmol) and N,O-dimethylhydroxylammonium chloride (146 mg,1.5 mmol) in DCM (10 mL) was added HATU(570 mg, 1.5 mmol) and DIPEA (516mg, 4 mmol). The resulting mixture was stirred at r.t. for 2 h. Theorganic phase was washed with 1N HCl (10 mL×3), sat. NaHCO₃ (20 mL×1)and brine, dried over Na₂SO₄ and concentrated under vacuum to give 390mg of the title compound as a white solid.

¹H NMR (CHLOROFORM-d) δ: 7.71-7.85 (m, J=8.3 Hz, 2H), 7.64 (s, 1H),7.39-7.50 (m, J=8.3 Hz, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=12.3 Hz,0.5H), 4.13-4.39 (m, 2.5H), 3.78-3.87 (m, 0.5H), 3.76 (br. s., 2H), 3.63(s, 3H), 3.58 (d, J=10.3 Hz, 0.5H), 3.35-3.46 (m, 6H), 3.23-3.34 (m,1H), 3.13 (br. s., 1H), 3.06 (d, J=12.5 Hz, 0.5H), 2.73 (br. s., 1H),2.61 (br. s., 1H), 2.00-2.12 (m, 1H), 1.35-1.47 (m, 1.5H), 1.24-1.35 (m,1.5H), 1.12-1.24 (m, 2H), 0.87-1.02 (m, 2H)

LC-MS: m/z 492.6 (M+H)⁺

Compound 714 (General Procedure 7)(R)-5-(bis(4-ethynylpyridin-2-yl)amino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.29 (d, J=5.1 Hz, 2H), 7.59 (s, 1H), 7.12 (br.s., 2H), 7.03 (dd, J=5.1, 1.1 Hz, 2H), 4.92 (br. s., 0.5H), 4.54 (d,J=13.2 Hz, 0.5H), 4.14-4.36 (m, 2.5H), 3.76 (t, J=6.2 Hz, 2.5H),3.49-3.66 (m, 0.5H), 3.39 (s, 3H), 3.20-3.35 (m, 3H), 3.14 (d, J=11.3Hz, 1H), 3.06 (d, J=11.3 Hz, 0.5H), 2.65-2.84 (m, 1H), 2.52-2.65 (m,1H), 1.86-1.99 (m, 1H), 1.22-1.38 (m, 3H), 0.95-1.08 (m, 2H), 0.68-0.82(m, 2H)

LC-MS: m/z 546.6 (M+H)⁺

Compound 713 (General Procedure 7)(R)-6-cyclopropyl-5-(4-ethynylpyridin-2-ylamino)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.12 (d, J=5.4 Hz, 1H), 7.78 (s, 1H), 6.82 (dd,J=5.4, 1.1 Hz, 1H), 6.61 (br. s., 1H), 6.52 (s, 1H), 4.92 (br. s.,0.5H), 4.54 (d, J=13.4 Hz, 0.5H), 4.07-4.32 (m, 2.5H), 3.68-3.87 (m,2.5H), 3.49-3.65 (m, 0.5H), 3.39 (s, 3H), 3.18-3.33 (m, 2H), 2.92-3.17(m, 1.5H), 2.64-2.83 (m, 1H), 2.53-2.64 (m, 1H), 2.08-2.22 (m, 1H), 1.41(d, J=6.2 Hz, 1.5H), 1.31 (d, J=6.4 Hz, 1.5H), 1.07-1.18 (m, 2H),0.96-1.07 (m, 2H)

LC-MS: m/z 445.5 (M+H)⁺

Compound 750 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(4-ethynylpyridin-2-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.00 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 6.88 (dd,J=5.9, 1.2 Hz, 1H), 6.64 (s, 1H), 4.51 (d, J=13.2 Hz, 1H), 4.37 (d,J=12.9 Hz, 1H), 4.17 (br. s., 2H), 4.01 (br. s., 0.5H), 3.89 (br. s.,0.5H), 3.71 (br. s., 0.5H), 3.40-3.52 (m, 4.5H), 3.22 (d, J=9.7 Hz, 1H),3.02-3.16 (m, 1H), 2.09-2.20 (m, 1H), 1.03-1.22 (m, 4H), 0.67 (br. s.,2H), 0.47 (br. s., 4H)

LC-MS: m/z 457.5 (M+H)⁺

Compound 647 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

To a solution of(R)-5-amino-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(140 mg, 0.41 mmol) and 2-chloro-4-vinylpyridine (57 mg, 0.41 mmol) in1,4-dioxane (15 mL) was added Pd2(dba)3 (56 mg, 0.061 mmol) and Xantphos(59 mg, 0.1 mmol) and Cs2CO3 (267 mg, 0.82 mmol) and the mixture washeated at 110° C. under N2. for 16 h. After TLC showed the completeconversion of starting material to product, the reaction mixture wasconcentrated and purified by column chromatography (DCM:MeOH=20:1) toafford 25 mg of title compound COMPOUND 647 and 20 mg compound COMPOUND646.

¹H NMR (CHLOROFORM-d) δ: 7.94-7.93 (d, 1H), 7.68 (s, 1H), 6.84-6.82 (d,1H), 6.58-6.51 (q, 1H), 6.38 (s, 1H), 5.95-5.90 (d, 1H), 5.55-5.52 (d,1H), 4.87 (s, 0.5H), 4.54-4.51 (d, 0.5H); 4.48-4.13 (m, 3H) 3.79-3.70(m, 2H) 3.44-3.35 (m, 1H) 3.25 (s, 3H), 3.11-2.98 (m, 3H), 2.77-2.56 (m,2H), 2.17-2.12 (m, 1H), 1.38-1.13 (m, 3H), 1.09-1.00 (m, 2H), 0.99-0.98(m, 2H).

LC-MS: m/z 447 (M+H)⁺

Compound 646 (General Procedure 7)(R)-5-(bis(4-vinylpyridin-2-yl)amino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.15-8.14 (d, 1H), 7.58 (s, 1H), 7.26-7.23 (d,1H), 6.97-6.94 (dd, 1H), 6.79-6.72 (q, 1H), 6.03-5.98 (dd, 1H), 5.58 (s,1H), 5.36-5.33 (dd, 1H), 4.88 (s, 0.5H), 4.54-4.51 (d, 0.5H); 4.20-4.09(dd, 2H) 3.93 (s, 2H) 3.75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m,2H), 2.18-2.10 (m, 1H), 1.41-1.26 (m, 3H), 1.43-1.30 (m, 2H), 1.13-1.11(m, 2H), 1.03-1.09 (m, 2H).

LC-MS: m/z 433 (M+H)⁺

Compound 706 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.13 (d, 1H), 7.85 (s, 1H), 6.83 (dd, 1.2 Hz,1H), 6.58 (dd, 10.7 Hz, 1H), 6.41 (s, 1H), 6.33 (br. s., 1H), 5.90 (d,1H), 5.46 (d, 0.5H), 4.36 (d, 1H), 4.26 (d, Hz, 1H), 4.00-4.15 (m,0.5H), 3.87 (d, 0.5H), 3.74 (t, 3H), 3.39 (s, 3H), 3.74-3.04 (m, 3H),2.48-2.77 (m, 2H), 2.14-2.25 (m, 1H), 1.39 (br. s., 1H), 1.14 (t, 2H),0.98-1.06 (m, 2H), 0.62-0.46 (d, 4H).

LC-MS: m/z 473 (M+H)⁺

Compound 754 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(2-vinylpyridin-4-ylamino)nicotinonitrile

¹H NMR (DMSO-d₆) δ: 8.08-8.20 (m, 1H), 7.92 (d, J=5.3 Hz, 1H), 6.67-6.84(m, 2H), 6.64 (br. s., 1H), 6.25 (d, J=16.7 Hz, 1H), 5.63 (br. s., 1H),4.56 (t, J=5.3 Hz, 1.5H), 4.08-4.52 (m, 4.5H), 3.94 (d, J=13.5 Hz, 1H),3.59-3.72 (m, 3.5H), 3.07-3.20 (m, 2H), 1.91-2.11 (m, 3H), 0.91-1.06 (m,8H), 0.74 (d, J=6.7 Hz, 3H)

LC-MS: m/z 461.6 (M+H)⁺

Compound 707 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.11 (d, 1H), 7.84 (s, 1H), 7.28 (s, 1H),6.74-6.92 (m, 1H), 6.67 (br. s., 1H), 6.58 (dd, 10.8 Hz, 1H), 6.41 (s,1H), 5.90 (d, 1H), 5.47 (d, 1H), 4.89 (br. s., 0.5H), 4.53 (d, 0.5H),4.07-4.36 (m, 2H), 3.93 (br. s., 2H), 3.72-3.65 (m, 1H), 2.98-3.27 (m,2.5H), 2.44-2.74 (m, 2.5H), 2.14-2.44 (m, 1H), 1.83-2.11 (m, 1.5H),1.21-1.50 (m, 1.5H), 0.96-1.20 (m, 2H), 0.90 (t, 2H).

LC-MS: m/z 433 (M+H)⁺

Compound 725 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methyl-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.07 (d, J=5.3 Hz, 1H), 6.88 (br. s., 1H), 6.79(dd, J=5.3, 1.2 Hz, 1H), 6.41-6.57 (m, 1H), 6.10 (s, 1H), 5.86 (d,J=17.6 Hz, 1H), 5.43 (d, J=10.9 Hz, 1H), 4.71-4.62 (m, 2-0.5H),4.16-4.34 (m, 2H), 4.07 (d, J=8.8 Hz, 0.5H), 3.92 (br. s., 3H), 3.77(br. s., 1H), 3.21-3.12 (d, 2H), 2.54-2.68 (m, 2H), 2.41 (s, 3H),2.14-2.31 (m, 1H), 1.03-1.13 (m, 2H), 0.89-1.01 (m, 2H), 0.32-0.57 (m,4H).

LC-MS: m/z 473 (M+H)⁺

Compound 682 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2-methoxypyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H),6.41-6.41 (d, 1H), 6.06 (s, 1H), 5.05 (m, 0.5H), 4.51-4.58 (m, 0.5H),4.14 (s, 3H), 4.12 (m, 0.5H), 3.85 (m, 2H), 3.54-3.52 (m, 0.5H); 3.28(s, 3H) 3.12-3.03 (m, 2H), 2.72-2.70 (m, 2H), 2.57-2.55 (m, 1H),1.38-1.36 (m, 1.5H), 1.32 (m, 1.5H), 1.26-1.25 (m, 2H), 1.09-1.05 (m,2H).

LC-MS: m/z 451 (M+H)⁺

Compound 683 (General Procedure 7) (R)-methyl4-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)amino)picolinate

¹H NMR (CHLOROFORM-d) δ: 8.35 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 6.82(s, 1H), 5.32-5.31 (m, 0.5H), 4.28-4.26 (m, 0.5H), 4.25-4.22 (m, 3H),3.96 (s, 3H), 4.12 (m, 3H), 3.37 (s, 3H), 3.03-3.28 (m, 2H), 2.61-2.58(m, 2H) 2.05-2.03 (m, 1H), 1.40-1.38 (m, 1.5H), 1.33-1.29 (m, 1.5H),1.27-1.25 (m, 2H), 1.11-0.99 (m, 2H).

LC-MS: m/z 479 (M+H)⁺

Compound 736 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((4-vinylpyrimidin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.36 (d, 1H), 8.30 (s, 1H), 7.02-7.13 (m, 1H),6.75 (d, 1H), 6.63 (dd, 10.6 Hz, 1H), 6.40 (d, 1H), 5.67 (d, 1H), 4.91(br. s., 0.5H), 4.54 (d, 0.5H), 4.23 (br. s., 0.5H), 4.00-4.17 (m, 2H),3.66-3.82 (m, 2H), 3.37-3.42 (m, 4H), 2.93-3.23 (m, 2H), 2.53-2.79 (m,2H), 2.08-2.20 (m, 1H), 1.38-1.45 (m, 1.5H), 1.31 (d, 1.5H), 1.09-1.17(m, 2H), 1.03 (dd, 2H).

LC-MS: m/z 448 (M+H)⁺

Compound 705 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinyl-1,8-naphthyridin-4-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.99 (br. s., 1H), 8.55 (d, J=7.8 Hz, 1H), 7.64(s, 1H), 7.39 (dd, J=8.3, 4.3 Hz, 1H), 6.82 (dd, J=17.1, 10.8 Hz, 1H),6.38 (br. s., 1H), 6.30 (d, J=17.6 Hz, 1H), 5.59 (d, J=10.8 Hz, 1H),4.91 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.26 (d, J=11.3 Hz, 2H),4.16 (d, J=13.3 Hz, 1H), 3.70-3.89 (m, 3H), 3.50-3.09 (m, 7H), 3.04 (d,J=12.3 Hz, 1H), 2.52-2.82 (m, 2.5H), 1.98-2.13 (m, 1.5H), 1.28-1.44 (m,5H), 0.93-1.02 (m, 2H)

LC-MS: m/z 498.1 (M+H)⁺

Compound 702(R)—N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-N-(pyridin-4-yl)acrylamide

Step 1:(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyridin-4-ylamino)nicotinonitrile

To a solution of(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(406 mg, 1 mmol) and pyridin-4-amine (94 mg, 1 mmol) in 1,4-dioxane (5mL) was added Pd(dba)₃ (136 mg, 0.15 mmol) and X-phos (72 mg, 0.15 mmol)and Cs₂CO₃ (752 mg, 2 mmol) at room temperature under N₂. The resultingmixture was heated and stirred at 120° C. under N₂ in microwave for 1.5h. The solvent was removed in vacuum and the residue was purified bycolumn chromatography (MeOH/DCM=1/15) afforded 168 mg of title compoundas a yellow solid.

LC-MS: m/z 471.4 (M+H)⁺

Step 2: Compound 702(R)—N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-N-(pyridin-4-yl)acrylamide

To a solution of(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyridin-4-ylamino)nicotinonitrile(41 mg, 0.1 mmol) and N,N-Diisopropylethylamine (26 mg, 0.2 mmol) in 5mL of DCM was added Acryloyl chloride (10 mg, 0.1 mmol) at roomtemperature. The reaction mixture was then stirred at room temperaturefor 3 h. After LC-MS showed the completion of reaction, the mixture waspoured into water and extracted with methylene chloride. The combinedorganic layer was dried over anhy. Na₂SO₄ and concentrated in vacuo.Column chromatography (MeOH/DCM=1/15) afforded 12.6 mg of title compoundas a colorless oil.

¹H NMR (CHLOROFORM-d) δ: 8.60 (d, J=4.8 Hz, 2H), 7.53 (s, 1H), 7.28 (s,2H), 6.58 (d, J=16.7 Hz, 1H), 6.16 (d, J=5.1 Hz, 1H), 5.82 (d, J=10.5Hz, 1H), 4.92 (m, 0.5H), 4.56 (m, 0.5H), 4.20-4.42 (m, 2H), 3.69-3.91(m, 2H), 3.58 (m, 1H), 3.37-3.41 (m, 3H), 3.36 (br. s., 1H), 3.14 (br.s., 2H), 2.59 (d, J=5.9 Hz, 2H), 1.82-1.94 (m, 1H), 1.37-1.44 (m, 2H),1.20-1.36 (m, 5H).

LC-MS: m/z 475.5 (M+H)⁺

Compound 712(R)—N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-N-(quinolin-4-yl)acrylamide

¹H NMR (CHLOROFORM-d) δ: 8.96 (d, J=4.5 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H),7.93-8.03 (m, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.44(br. s., 1H), 7.30 (br. s., 1H), 6.61 (d, J=16.8 Hz, 1H), 6.16 (d,J=5.10 Hz, 1H), 5.82 (d, J=10.48 Hz, 1H), 4.88 (m, J=10.48 Hz, 0.5H),4.52 (m, J=6.48 Hz, 0.5H), 4.27 (t, J=12.9 Hz, 2H), 3.74 (t, J=6.1 Hz,2H), 3.52 (m, J=9.1 Hz, 1H), 3.37 (s, 3H), 3.29 (d, J=10.8 Hz, 1H), 3.12(br. s., 2H), 2.72 (t, J=9.8 Hz, 1H), 2.58 (t, J=5.8 Hz, 1H), 2.23 (t,J=7.7 Hz, 1H), 1.31-1.40 (m, 2H), 1.21-1.31 (m, 3H), 1.14 (br. s., 2H).

LC-MS: m/z 525.5 (M+H)⁺

Compound 732 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinolin-7-ylamino)nicotinonitrile

To a solution of(R)-5-amino-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile(34 mg, 0.1 mmol) and 7-bromo-2-vinylquinoline (23 mg, 0.1 mmol) in1,4-dioxane (1 mL) was added Pd(dba)₃ (13.6 mg, 0.015 mmol) and X-phos(7.2 mg, 0.15 mmol) and Cs₂CO₃ (75.2 mg, 0.2 mmol) at room temperatureunder N₂. The resulting mixture was heated and stirred at 120° C. underN₂ in microwave for 1.5 h. The solvent was removed in vacuum and theresidue was purified by column chromatography (MeOH/DCM=1/15) afforded17.2 mg of title compound as a colorless oil.

¹H NMR (CHLOROFORM-d) δ: 8.08 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H),7.64 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.31 (br. s., 1H), 7.03-7.18 (m,2H), 6.32 (d, J=17.6 Hz, 1H), 6.18 (br. s., 1H), 5.74 (d, J=10.9 Hz,1H), 4.92 (m, 0.5H), 4.54 (m, 0.5H), 4.09-4.33 (m, 2H), 3.71-3.86 (m,2H), 3.57 (br. s., 1H), 3.40 (s, 3H), 3.25 (t, J=11.4 Hz, 1H), 3.13 (br.s., 2H), 2.75 (br. s., 1H), 2.53-2.64 (m, 1H), 2.14-2.27 (m, 1H),1.40-1.47 (m, 1H), 1.24-1.35 (m, 2H), 1.12 (t, J=3.7 Hz, 2H), 0.97 (dd,J=7.9, 3.5 Hz, 2H).

LC-MS: m/z 497.4 (M+H)⁺

Compound 665(R)-methyl-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)benzoate

1H NMR (CHLOROFORM-d) δ 8.12 (d, J=7.5 Hz, 2H), 7.63 (br. s., 1H), 7.48(d, J=7.5 Hz, 2H), 4.47-4.61 (d, J=12.5 Hz, 0.5H), 4.19-4.37 (m, 2.5H),3.96 (br. s., 3H), 3.75 (br. s., 2H), 3.47-3.61 (m, 1H), 3.38 (br. s.,3H), 3.28 (br. s., 1H), 3.01-3.18 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (br.s., 1H), 1.96-2.10 (m, 1H), 1.72-1.91 (m, 1H), 1.38 (br. s., 1H), 1.28(br. s., 2H), 1.18 (br. s., 2H), 0.97 (br. s., 2H)

LC-MS: m/z 463.2 (M+H)⁺

Compound 704 (General Procedure 8)(R)-5-((2-chloropyridin-4-yl)oxy)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.29 (d, J=5.7 Hz, 1H), 7.47 (s, 1H), 6.83-6.77(m, 2H), 4.90-4.91 (m, 1H), 4.53-4.55 (m, 1H), 4.20 (t, J=12.8 Hz, 3H),3.92 (s, 2H), 3.79-3.70 (m, 1H), 3.55 (d, J=10.9 Hz, 1H), 3.31-3.20 (m,1H), 3.14-2.99 (m, 1H), 2.55 (s, 2H), 2.01 (t, J=4.6 Hz, 1H), 1.87 (d,J=3.4 Hz, 1H), 1.43 (d, J=6.4 Hz, 1H), 1.32 (d, J=6.4 Hz, 2H), 1.12 (dd,J=7.9, 3.1 Hz, 2H), 1.03 (dt, J=7.9, 3.1 Hz, 2H).

LC-MS: m/z 442.1 (M+H)⁺

Compound 695 (General Procedure 8)(R)-5-((2-chloropyridin-4-yl)oxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.29 (d, J=5.6 Hz, 1H), 7.46 (s, 1H), 6.83-6.76(m, 2H), 4.69-4.72 (m, 0.5H), 4.40 (d, J=12.6 Hz, 1H), 4.28 (d, J=12.7Hz, 1H), 4.13 (dd, J=14.3, 7.2 Hz, 1H), 3.88 (d, J=12.0 Hz, 1H),3.78-3.64 (m, 3H), 3.38 (s, 3H), 3.18 (d, J=13.1 Hz, 1H), 3.04 (d,J=26.4 Hz, 1H), 2.74-2.57 (m, 2H), 2.48-2.50 (m, 0.5H), 1.98-2.04 (m,1H), 1.35 (t, J=10.7 Hz, 1H), 1.13 (dd, J=7.4, 3.1 Hz, 2H), 1.02 (dt,J=7.9, 3.1 Hz, 2H), 0.59 (d, J=30.2 Hz, 2H), 0.45-0.48 (m, 2H).

LC-MS: m/z 482.1 (M+H)⁺

Compound 694 (General Procedure 8)(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

A mixture of(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile(3, general procedure 8 scheme) (0.35 g, 0.88 mol), sodium3-hydroxypropanoate (0.10 g, 0.88 mol), HATU (0.5 g, 1.32 mmol) and 0.23g DIEA (1.76 mmol) was stirred in 8 mL DMF for 4 hrs. Then the mixturewas quenched by adding 6 mL water and extracted with EtOAc (15 mL×2),the organic phase was combined and concentrated to give a yellow oil,which was further purified by silica gel chromatography (DCM:MeOH=20:1)to give 0.10 g of product as yellow solid (52% yield).

¹H NMR (CHLOROFORM-d) δ: 8.30 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H),6.81 (dt, J=5.6, 2.0 Hz, 2H), 4.70 (s, 1H), 4.41 (d, J=13.0 Hz, 1H),4.29 (d, J=13.0 Hz, 1H), 4.12 (dd, J=18.6, 7.4 Hz, 1H), 3.93 (s, 2H),3.84-3.67 (m, 1H), 3.18 (d, J=12.8 Hz, 1H), 3.13-2.99 (m, 1H), 2.61 (s,2H), 2.32-2.22 (m, 0.5H), 2.02 (t, J=4.6 Hz, 1H), 1.35 (s, 1H), 1.29 (d,J=9.4 Hz, 3H), 1.14 (dd, J=7.4, 3.0 Hz, 2H), 1.04 (dt, J=7.9, 3.1 Hz,2H), 0.66-0.67 (m, 2H), 0.46-0.51 (m, 2H).

LC-MS: m/z 468.1 (M+H)⁺

Compound 692 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(2-vinylpyridin-4-yloxy)nicotinonitrile

A mixture of(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (4) 0.35 g, (0.75 mmol),potassium trifluoro(vinyl)borate (0.15 g, 1.1 mmol), PdCl₂dppf (80 mg,0.075 mmol) and DIEA (0.24 mL, 1.5 mmol) was heated in isopropanol atreflux at 85° C. under nitrogen for 5 hrs. The mixture was thenconcentrated under reduced pressure to give a yellow solid which wasfurther purified by silica chromatography (PE/EA/MeOH=150/120/8) to give0.19 g of product as a white solid (55% yield).

¹H NMR (CHLOROFORM-d) δ:8.47 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H),6.86 (d, J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6,2.4 Hz, 1H), 6.22 (dd, J=17.4, 0.9 Hz, 1H), 5.53 (dd, J=10.8, 0.8 Hz,1H), 4.68 (d, J=11.7 Hz, 1H), 4.38 (d, J=12.9 Hz, 1H), 4.30-4.22 (m,1H), 4.15-4.04 (m, 1H), 3.92 (s, 2H), 3.75 (d, J=20.7 Hz, 1H), 3.47 (d,J=21.7 Hz, 1H), 3.25-3.12 (m, 1H), 3.09-2.95 (m, 1H), 2.60 (s, 2H),2.32-2.22 (m, 0.5H), 2.11-2.05 (m, 1H), 1.37 (d, J=20.5 Hz, 1H), 1.27(d, J=2.0 Hz, 1H), 1.16-1.10 (m, 2H), 1.01 (ddd, J=10.1, 6.7, 3.3 Hz,2H), 0.65 (t, J=33.7 Hz, 2H), 0.45-0.48 (m, 2H).

LC-MS: m/z 460.1 (M+H)⁺

Compound 693 (General Procedure 8)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(2-vinylpyridin-4-yloxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.46 (d, J=5.6 Hz, 1H), 7.46 (s, 1H), 6.86 (d,J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz,1H), 6.22 (d, J=17.4 Hz, 1H), 5.53 (d, J=10.9 Hz, 1H), 4.54-4.71 (m,0.5H), 4.37 (d, J=12.4 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.11 (s, 1H),3.88 (d, J=11.9 Hz, 1H), 3.80-3.68 (m, 3H), 3.38 (s, 3H), 3.20 (t,J=23.2 Hz, 1H), 3.05 (s, 1H), 2.68 (dd, J=15.1, 12.2 Hz, 2H), 2.47-2.53(m, 0.5H), 2.06 (dd, J=8.6, 3.9 Hz, 1H), 1.38-1.28 (m, 1H), 1.13 (dd,J=7.4, 3.1 Hz, 2H), 1.01 (dt, J=7.9, 3.2 Hz, 2H), 0.73-0.51 (m, 2H),0.43-0.46 (m, 2H).

LC-MS: m/z 476.1 (M+H)⁺

Compound 668 (General Procedure 8)(R)-5-((2-chloropyridin-4-yl)oxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.47 (s, 1H), 6.85 (s, 2H),4.93-5.05 (m, 0.5H), 4.56-4.58 (m, 0.5H), 4.33-4.09 (m, 3H), 3.88-3.68(m, 3H), 3.57 (s, 1H), 3.40 (s, 3H), 3.30 (s, 1H), 3.10 (dd, J=36.0,11.2 Hz, 1H), 2.82-2.48 (m, 1H), 1.42 (d, J=6.5 Hz, 2H), 1.36-1.29 (m,2H), 1.14 (s, 2H), 1.03-1.05 (m, 2H).

LC-MS: m/z 456.0 (M+H)⁺

Compound 666 (General Procedure 8)(R)-5-((6-chloropyrimidin-4-yl)oxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.47 (s, 1H), 6.85 (s, 2H),4.92-4.96 (m, 0.5H), 4.55-4.58 (m, 0.5H), 4.33-4.09 (m, 3H), 3.88-3.68(m, 2H), 3.57 (s, 1H), 3.40 (s, 3H), 3.30 (s, 1H), 3.10 (dd, J=36.0,11.2 Hz, 1H), 2.82-2.48 (m, 1H), 1.42 (d, J=6.5 Hz, 2H), 1.36-1.29 (m,2H), 1.14 (s, 2H), 1.03 (d, J=4.1 Hz, 2H).

LC-MS: m/z 449.0 (M+H)⁺

Compound 734 (General Procedure 8)(R)-5-((4-chloropyridin-2-yl)oxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.07 (d, J=6.0 Hz, 1H), 7.54 (s, 1H), 7.09-7.05(m, 2H), 4.60-4.68 (m, 1H), 4.31-4.35 (m, 1H), 4.21 (d, J=13.0 Hz, 1H),4.07 (d, J=9.8 Hz, 1H), 3.92 (s, 2H), 3.74 (d, J=11.5 Hz, 1H), 3.48 (d,J=24.4 Hz, 1H), 3.21-3.07 (m, 1H), 3.03 (d, J=10.9 Hz, 1H), 2.58 (d,J=17.5 Hz, 2H), 2.15-2.00 (m, 1H), 1.44 (s, 1H), 1.13 (dd, J=7.3, 3.6Hz, 2H), 0.98 (dt, J=6.8, 2.7 Hz, 2H), 0.65 (s, 2H), 0.45-0.48 (m, 2H).

LC-MS: m/z 469.2 (M+H)⁺

Compound 733 (General Procedure 8)(R)-5-((4-chloropyridin-2-yl)oxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.10 (d, J=5.3 Hz, 1H), 7.53 (s, 1H), 7.07 (dd,J=5.3, 1.1 Hz, 1H), 6.97 (s, 1H), 6.70 (dd, J=17.6, 10.9 Hz, 1H), 6.01(d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.69-4.71 (m, 0.5H), 4.28(d, J=12.4 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 4.09 (d, J=8.0 Hz, 1H),3.80-3.90 (m, 0.5H), 3.72 (dd, J=13.7, 7.8 Hz, 3H), 3.39 (d, J=5.9 Hz,3H), 3.27 (s, 1H), 3.09 (d, J=12.5 Hz, 1H), 2.97 (s, 1H), 2.73-2.59 (m,2H), 2.18-2.10 (m, 1H), 1.12 (d, J=4.0 Hz, 2H), 0.96 (ddd, J=9.2, 8.5,5.1 Hz, 3H), 0.89 (dd, J=13.9, 6.8 Hz, 2H), 0.62 (s, 2H), 0.45-0.47 (m,2H).

LC-MS: m/z 474.2 (M+H)⁺

Compound 832 (General Procedure 8)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2-vinylpyridin-4-yl)oxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.47 (d, J=5.6 Hz, 1H), 7.44 (d, J=3.5 Hz, 1H),6.88 (s, 1H), 6.84-6.74 (m, 1H), 6.69 (d, J=3.5 Hz, 1H), 6.28 (d, J=17.4Hz, 1H), 5.58 (d, J=10.7 Hz, 1H), 4.89-4.91 (m, 0.5H), 4.50-4.54 (m,0.5H), 4.23-4.06 (m, 2H), 3.82-3.68 (m, 2H), 3.50-3.53 (m, 0.5H), 3.37(s, 3H), 3.26 (d, J=12.7 Hz, 1H), 3.05-3.10 (m, 1.5H), 2.78-2.52 (m,2H), 2.05-1.93 (m, 1H), 1.39 (d, J=6.0 Hz, 1H), 1.32-1.25 (m, 3H),1.14-1.08 (m, 2H), 0.99 (dt, J=11.5, 3.3 Hz, 2H).

LC-MS: m/z 448.0 (M+H)⁺

Compound 703 (General Procedure 8)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2-vinylpyridin-4-yl)methoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.61 (d, J=5.0 Hz, 1H), 7.39 (s, 1H), 7.21-7.26(m, 1H), 7.18 (s, 1H), 6.85 (dd, J=17.4, 10.9 Hz, 1H), 6.26 (dd, J=17.4,1.1 Hz, 1H), 5.47-5.61 (m, 1H), 5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.52(d, J=13.6 Hz, 0.5H), 4.21 (d, J=6.8 Hz, 0.5H), 3.85-4.05 (m, 2H),3.67-3.81 (m, 2.5H), 3.54 (d, J=6.8 Hz, 0.5H), 3.37 (s, 3H), 3.04-3.18(m, 1.5H), 2.84-3.04 (m, 1H), 2.63-2.80 (m, 1H), 2.44-2.63 (m, 2H),1.22-1.36 (m, 3H), 1.03-1.17 (m, 4H)

LC-MS: m/z 461.6 (M+H)⁺

Compound 7895-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methylnicotinonitrile

1H NMR (CHLOROFORM-d) 6.67 (dd, J=16.7, 10.6 Hz, 1H), 6.35 (dd, J=16.7,7.0 Hz, 1H), 5.64-5.85 (m, 2H), 5.26 (m, 6.6 Hz, 1H), 4.66-4.79 (m, 1H),4.56 (br. s., 1H), 4.23-4.39 (m, 2H), 4.18 (d, J=12.6 Hz, 1H), 3.95-4.11(m, 2H), 3.90 (d, J=17.9 Hz, 1H), 3.63-3.83 (m, 2H), 3.27 (br. s., 1H),3.08 (br. s., 1H), 2.96 (d, J=10.3 Hz, 2H), 2.79-2.92 (m, 2H), 2.53 (d,J=7.9 Hz, 1H), 2.31-2.48 (m, 5H), 2.04 (dd, J=13.4, 6.0 Hz, 1H), 1.44(d, J=8.2 Hz, 1H), 1.15 (br. s., 1H), 0.85-1.07 (m, 3H), 0.60 (br. s.,1H), 0.52 (br. s., 1H), 0.44 (br. s., 2H)

LC-MS: m/z 516.6 (M+H)

Compound 7786-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-5-(1-methyl-6-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) 7.86-7.94 (s, 1H), 7.71-7.81 (s, 1H), 7.22 (s,1H), 6.99 (dd, J=17.6, 10.9 Hz, 1H), 6.28-6.48 (m, 1H), 5.66 (dd,J=10.9, 0.9 Hz, 1H), 5.28 (t, J=6.7 Hz, 1H), 4.68-4.78 (m, 1H),4.54-4.68 (m, 2H), 4.48 (d, J=14.1 Hz, 1H), 4.21 (s, 3H), 3.75-4.17 (m,2H), 2.77-3.35 (m, 6H), 2.45-2.65 (m, 1H), 1.85-2.01 (m, 2H), 1.18-1.25(m, 2H), 0.95-1.05 (m, 2H), 0.61-0.81 (m, 1H), 0.57 (br. s., 1H), 0.48(br. s., 2H)

LC-MS: m/z 524.2 (M+H)⁺

Compound 777(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methyl-5-((2-vinylpyridin-4-yl)oxy)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=5.7 Hz, 1H), 6.93-6.75 (m, 2H),6.65 (d, J=3.7 Hz, 1H), 6.30 (d, J=17.4 Hz, 1H), 5.60 (d, J=10.7 Hz,1H), 4.60-4.71 (m, 0.5H), 4.27-4.28 (m, 1H), 4.23-4.14 (m, 1H),4.10-4.15 (m, 0.5H), 3.92-3.93 (m, 2H), 3.78-3.79 (m, 1H), 3.44-3.45 (m,1H), 3.26-3.10 (m, 1H), 3.04-3.05 (m, 1H), 2.61-2.62 (m, 2H), 2.31 (s,3H), 2.01-1.94 (m, 1H), 1.44-1.45 (m, 1H), 1.13-1.07 (m, 2H), 1.01-0.94(m, 2H), 0.91-0.86 (m, 1H), 0.65-0.66 (m, 1H), 0.46-0.52 (m, 2H). MS(ES) M+H expected 474.0, found 474.6

Compound 833(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-((5-vinylpyridazin-3-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 7.76 (s, 1H), 6.58 (dd, J=17.6,11.0 Hz, 2H), 6.05 (d, J=17.6 Hz, 1H), 5.66 (d, J=11.0 Hz, 1H),4.65-4.70 (m, 0.5H), 4.43-4.46 (m, 1H), 4.33 (d, J=12.4 Hz, 1H),4.16-4.07 (m, 1H), 3.87-3.88 (m, 0.5H), 3.71-3.74 (m, 3H), 3.39 (s, 3H),3.20 (s, 1H), 3.07-3.09 (m, 1H), 2.65-2.66 (m, 2H), 2.55-2.47 (m, 1H),2.18 (d, J=10.1 Hz, 1H), 1.30-1.25 (m, 1H), 1.15 (s, 2H), 1.07-0.98 (m,2H), 0.50-0.60 (m, 2H), 0.45-0.47 (m, 2H). MS (ES) M+H expected 474.0,found 474.6

Compound 792(R)-5-(4-cyanopyridin-2-ylamino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (400 MHz, CHLOROFORM-d) δ: 8.31 (d, J=5.0 Hz, 1H), 7.80-7.69 (m,1H), 6.94 (dd, J=1.3, 5.1 Hz, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.34 (d,J=12.6 Hz, 2H), 4.14-3.65 (m, 4H), 3.39 (s, 3H), 2.61-3.23 (m, 5H),2.15-2.05 (m, 1H), 1.20-1.11 (m, 2H), 1.04 (td, J=3.0, 7.8 Hz, 2H), 0.45(d, J=5.3 Hz, 5H) LC_MS (M+1)⁺472.5

Compound 7834-(5-cyano-2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)pyridin-3-ylamino)picolinonitrile

¹H NMR (400 MHz, CHLOROFORM-d) δ: 8.30 (d, J=5.9 Hz, 1H), 7.59 (s, 1H),6.92 (d, J=2.3 Hz, 1H), 6.77-6.62 (m, 2H), 5.27 (t, J=6.7 Hz, 1H),4.75-4.65 (m, 1H), 4.62-4.51 (m, 1H), 4.47 (d, J=12.6 Hz, 1H), 4.37 (d,J=12.6 Hz, 1H), 4.07 (d, J=7.9 Hz, 1H), 3.65-3.75 (m, 1H), 3.30-3.04 (m,2H), 2.98 (s, 1H), 2.92-2.72 (m, 3H), 2.62-2.44 (m, 1H), 2.05-1.98 (m,1H), 1.08-0.99 (m, 2H), 0.93-0.80 (m, 4H), 0.63 (br. s., 1H), 0.52 (br.s., 1H), 0.48-0.36 (m, 1H)

LC_MS (M+1)⁺484.6

Compound 7746-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((S)-oxetan-2-yl)acetyl)piperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.23 (d, J=5.9 Hz, 1H), 7.62 (s, 1H), 6.72 (dd,J=17.4, 10.9 Hz, 1H), 6.63 (s, 1H), 6.55 (s, 1H), 6.26 (d, J=17.6 Hz,1H), 5.54 (d, J=10.7 Hz, 1H), 5.34-5.22 (m, 1H), 4.73 (dd, J=14.6, 8.2Hz, 1H), 4.56 (dt, J=9.1, 5.8 Hz, 1H), 4.47 (d, J=12.9 Hz, 1H), 4.34 (d,J=13.2 Hz, 1H), 4.09 (d, J=10.0 Hz, 0.5H), 3.89 (d, J=13.3 Hz, 0.5H),3.80-0.64 (m, 1H), 3.42-3.15 (m, 2H), 3.15-2.78 (m, 3H), 2.75-2.34 (m,2H), 2.10 (ddd, J=12.7, 8.1, 4.7 Hz, 1H), 1.29 (dd, J=6.7, 4.8 Hz, 1H),1.18-1.10 (m, 2H), 1.03 (dd, J=7.7, 3.2 Hz, 2H), 0.81-0.53 (m, 2H),0.52-0.38 (m, 2H).

LC-MS: m/z NB295-063-01 485.1 (M+H)⁺

Compound 791(R,E)-6-cyclopropyl-2-(4-(5-hydroxypent-2-enoyl)-3-isopropylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.10 (d, J=5.3 Hz, 1H), 7.81 (s, 1H), 6.90 (tt,J=14.6, 7.3 Hz, 1H), 6.82 (d, J=5.3 Hz, 1H), 6.79-6.63 (m, 1H), 6.58(dd, J=17.6, 10.8 Hz, 1H), 6.41 (d, J=14.1 Hz, 2H), 5.89 (d, J=17.5 Hz,1H), 5.46 (d, J=10.8 Hz, 1H), 4.76-4.64 (m, 0.5H), 4.55-4.37 (m, 1.5H),4.26 (t, J=11.6 Hz, 1H), 4.18 (d, J=5.2 Hz, 0.5H), 3.95 (d, J=13.7 Hz,0.5H), 3.81 (t, J=6.0 Hz, 2H), 3.67 (d, J=9.3 Hz, 0.5H), 3.54-3.42 (m,0.5H), 3.29-3.16 (m, 0.5H), 3.16-2.96 (m, 2.5H), 2.52 (dd, J=13.0, 6.4Hz, 2H), 2.36-2.24 (m, 0.5H), 2.24-2.11 (m, 1.5H), 1.18-1.08 (m, 2H),1.07 (d, J=6.5 Hz, 3H), 1.04-0.98 (m, 2H), 0.93-0.84 (m, 3H).

LC-MS: m/z NB295-055-02 487.7 (M+H)⁺

Compound 790(R)-6-cyclopropyl-2-(4-(5-hydroxypent-2-enoyl)-3-isopropylpiperazin-1-yl)-5-(2-vinylquinoxalin-5-yl)nicotinonitrile

¹H NMR (400 MHz, CHLOROFORM-d) δ: 9.02 (s, 1H), 8.19-8.09 (m, 1H),7.91-7.80 (m, 1 H), 7.76-7.67 (m, 2H), 7.08 (dd, J=11.2, 17.6 Hz, 1H),6.98-6.82 (m, 0.5H), 6.57-6.37 (m, 1.5H), 5.97-5.73 (m, 2H), 4.70-4.35(m, 3.5H), 4.23-4.16 (m, 1H), 3.86-3.75 (m, 1.5H), 3.60-3.42 (m, 1H),3.32-3.05 (m, 4H), 2.58-2.48 (m, 1H), 2.37-2.18 (m, 1H), 1.32-1.23 (m,2H), 1.16-1.05 (m, 3H), 0.98-0.72 (m, 6H)

LC_MS (M+1)⁺523.7

Compound 7942-cyclopropyl-6-((R)-3-cyclopropyl-4-(3-((R)-oxetan-2-yl)propanoyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.63 (d, J=5.3 Hz, 1H), 7.63 (s, 1H), 7.38 (s,1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.86 (dd, J=17.3, 10.9 Hz, 1H), 6.26(d, J=17.3 Hz, 1H), 5.55 (d, J=10.9 Hz, 1H), 4.86 (s, 1H), 4.60-4.74 (m,1H), 4.46-4.60 (m, 2H), 4.40 (d, J=12.9 Hz, 1H), 4.07 (s, 1H), 3.82 (s,1H), 3.69 (s, 1H), 3.12-3.42 (m, 2H), 2.99-3.10 (m, 1H), 2.48-2.63 (m,3H), 1.96-2.24 (m, 3H), 1.19 (m, 2H), 0.93-1.02 (m, 2H), 0.33-0.54 (m,4H)

LC-MS: m/z 484.3 (M+H)⁺

Compound 7856-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.01 (d, J=1.8 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H),7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.79 (d, J=11.2Hz, 1H), 5.27 (t, J=6.7 Hz, 1H), 4.66-4.79 (m, 1H), 4.51-4.63 (m, 1H),4.41 (d, J=12.6 Hz, 1H), 4.09 (d, J=7.6 Hz, 1H), 3.95 (d, J=12.6 Hz,1H), 3.79 (d, J=10.9 Hz, 1H), 2.92-3.32 (m, 4H), 2.84-2.92 (m, 1H),2.46-2.61 (m, 1H), 2.24 (s, 3H), 2.04 (dd, J=15.1, 7.5 Hz, 1H),1.43-1.50 (m, 1H), 1.09-1.19 (m, 2H), 0.83-0.91 (m, 2H), 0.35-0.62 (m,4H)

LC-MS: m/z 485.3 (M+H)⁺

Compound 7866-cyclopropyl-2-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.01 (s, 1H), 7.50 (s, 1H), 7.12 (dd, J=17.9,11.2 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.78 (d, J=11.2 Hz, 1H),5.23-5.31 (m, 1H), 4.64-4.78 (m, 1H), 4.39-4.63 (m, 3H), 4.34 (d, J=12.6Hz, 1H), 3.91 (d, J=13.5 Hz, 1H), 3.43-3.65 (m, 1H), 2.92-3.17 (m, 4H),2.82-2.91 (m, 1H), 2.44-2.66 (m, 1H), 2.22 (s, 3H), 2.07-2.17 (m, 1H),1.91-2.04 (m, 1H), 1.38-1.58 (m, 1H), 1.00-1.15 (m, 3H), 0.85-0.94 (m,6H)

LC-MS: m/z 487.3 (M+H)⁺

Compound 776(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.01 (d, J=1.8 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H),7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.37 (d, J=17.6 Hz, 1H), 5.80 (d, J=11.2Hz, 1H), 4.41 (d, J=13.2 Hz, 1H), 4.32 (d, J=12.9 Hz, 1H), 4.09 (d,J=7.0 Hz, 1H), 3.93 (s, 2H), 3.68-3.84 (m, 2H), 3.13-3.37 (m, 2H), 3.09(d, J=8.5 Hz, 1H), 2.54-2.67 (m, 2H), 2.24 (s, 3H), 1.45-1.49 (m, 1H),1.07-1.19 (m, 2H), 0.92 (dd, J=12.5, 6.3 Hz, 2H), 0.47-0.67 (m, 4H)

LC-MS: m/z 459.2 (M+H)⁺

Compound 7936-cyclopropyl-2-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.27 (br. s., 1H), 7.43 (br. s., 1H), 6.73 (dd,J=17.6, 11.2 Hz, 1 H), 6.20 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H),5.28 (m, 1H), 4.63-4.78 (m, 1H), 4.30-4.60 (m, 3.5H), 3.87 (d, J=13.2Hz, 0.5H), 3.41-3.61 (m, 1H), 2.88-3.18 (m, 4H), 2.72-2.88 (m, 2H),2.41-2.65 (m, 1H), 2.22 (s, 3H), 2.01-2.16 (m, 1H), 1.38-1.51 (m, 1H),1.12 (d, J=16.4 Hz, 2H), 0.98-1.05 (m, 3H), 0.75-0.98 (m, 6H)

LC-MS: m/z 487.1 (M+H)

Compound 784(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.28 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H),6.75 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.79 (d, J=11.2Hz, 1H), 4.40-4.55 (m, 1.5H), 4.35 (d, J=11.2 Hz, 1H), 3.94 (t, J=4.8Hz, 2H), 3.67-3.81 (m, 0.5H), 3.41-3.57 (m, 1H), 3.01-3.21 (m, 3H),2.57-2.66 (m, 2H), 2.28 (s, 3H), 1.63-1.67 (m, 1H), 1.12-1.16 (m, 2H),1.01-1.09 (m, 3H), 0.79-0.98 (m, 6H)

LC-MS: m/z 461.1 (M+H)

Compound 7806-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((S)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.27 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H),6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9Hz, 1H), 5.20-5.29 (m, 1H), 4.68-4.78 (m, 1H), 4.51-4.68 (m, 1H), 4.43(d, J=12.9 Hz, 1H), 4.33 (d, J=12.0 Hz, 1H), 4.07 (d, J=9.1 Hz, 0.5H),3.81-3.93 (m, 0.5H), 3.69-3.81 (m, 0.5H), 3.09-3.28 (m, 3.5H), 2.81-3.01(m, 3H), 2.55 (m, 1H), 2.30 (s, 3H), 1.82 (br. s., 1H), 1.41-1.54 (m,1H), 1.15 (br. s., 2H), 0.88 (m, 2H), 0.43-0.72 (m, 4H)

LC-MS: m/z 485.1 (M+H)

Compound 779(R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridin]-2′-yltrifluoromethanesulfonate

¹H NMR (CHLOROFORM-d) δ 8.49 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.46 (dd,J=5.1, 1.3 Hz, 1H), 7.23-7.28 (m, 1H), 4.92 (br. s., 0.5H), 4.55 (d,J=10.3 Hz, 0.5H), 4.23-4.47 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65(m, 0.5H), 3.31-3.45 (m, 4H), 3.05-3.29 (m, 1.5H), 2.64-2.80 (m, 1H),2.53-2.64 (m, 1H), 1.90-2.03 (m, 1H), 1.38 (d, J=6.2 Hz, 1.5H),1.18-1.33 (m, 3.5H), 1.02-1.13 (m, 2H)

LC-MS: m/z 554.1 (M+H)

Compound 773(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.02 (s, 1H), 7.52 (s, 1H), 7.14 (dd, J=17.6,11.2 Hz, 1H), 6.37 (d, J=17.9 Hz, 1H), 5.80 (d, J=11.2 Hz, 1H),4.65-4.76 (m, 0.5H), 4.40-4.55 (m, 1.5H), 4.34 (t, J=10.4 Hz, 1H),3.86-4.01 (m, 2H), 3.77 (d, J=13.5 Hz, 0.5H), 3.42-3.57 (m, 1H),2.96-3.21 (m, 3H), 2.53-2.69 (m, 2H), 2.20 (s, 3H), 1.42-1.50 (m, 1H),1.10-1.16 (m, 2H), 1.00-1.08 (m, 3H), 0.83-1.00 (m, 6H)

LC-MS: m/z 461.1 (M+H)

Compound 771 (R)-tert-butyl4-(3-cyano-6-cyclopropyl-4-methyl-5-(5-vinylpyridazin-3-yl)pyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate

¹H NMR (CHLOROFORM-d) δ 9.28 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H),6.75 (dd, J=17.8, 11.0 Hz, 1H), 6.15-6.26 (m, 1H), 5.79 (d, J=10.9 Hz,1H), 4.41 (d, J=12.9 Hz, 1H), 4.31 (d, J=12.6 Hz, 1H), 4.08 (d, J=14.4Hz, 1H), 3.36-3.55 (m, 2H), 3.24 (dd, J=12.9, 3.5 Hz, 1H), 3.07 (td,J=12.5, 3.5 Hz, 1H), 2.24 (s, 3H), 1.54 (s, 9H), 1.41-1.47 (m, 1H),1.31-1.39 (m, 1H), 1.16 (br. s., 2H), 0.79-0.96 (m, 2H), 0.42-0.66 (m,3H), 0.28-0.42 (m, 1H)

LC-MS: m/z 487.1 (M+H)

Compound 772 (R)-tert-butyl4-(3-cyano-6-cyclopropyl-4-methyl-5-(6-vinylpyridazin-4-yl)pyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate

¹H NMR (CHLOROFORM-d) δ ¹H NMR (CHLOROFORM-d): 9.27 (d, J=2.1 Hz, 1H),7.44 (d, J=2.1 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.21 (d, J=17.6Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 4.41 (d, J=12.9 Hz, 1H), 4.30 (d,J=12.6 Hz, 1H), 4.02-4.22 (m, 1H), 3.36-3.53 (m, 2H), 3.18-3.30 (m, 1H),3.07 (td, J=12.4, 3.4 Hz, 1H), 2.23 (s, 3H), 1.49 (s, 9H), 1.42-1.48 (m,1H), 1.31-1.38 (m, 1H), 1.09-1.21 (m, 2H), 0.87 (dd, J=7.8, 3.1 Hz, 2H),0.42-0.65 (m, 3H), 0.30-0.42 (m, 1H)

LC-MS: m/z 487.1 (M+H)

Compound 769(R,E)-6-cyclopropyl-2-(3-cyclopropyl-4-(5-hydroxypent-2-enoyl)piperazin-1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.27 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H),6.87 (dt, J=14.8, 7.3 Hz, 1H), 6.73 (dd, J=17.8, 11.0 Hz, 1H), 6.26-6.49(m, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 4.42 (d,J=12.9 Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 4.04-4.21 (m, 1H), 3.79 (t,J=6.0 Hz, 3H), 3.38 (br. s., 1H), 3.23 (d, J=10.0 Hz, 1H), 3.08 (td,J=12.5, 2.9 Hz, 1H), 2.50 (q, J=6.2 Hz, 2H), 2.27 (s, 3H), 1.35-1.52 (m,2H), 1.15 (br. s., 2H), 0.88 (dd, J=7.6, 3.2 Hz, 2H), 0.65 (br. s., 1H),0.51 (br. s., 1H), 0.44 (br. s., 2H)

LC-MS: m/z 485.1 (M+H)

Compound 770(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(4-hydroxybutanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) 8.69 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d,J=5.0 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H),5.57 (dd, J=10.7, 1.0 Hz, 1H), 4.33 (d, J=12.9 Hz, 1H), 4.25 (d, J=12.6Hz, 1H), 4.09 (d, J=7.6 Hz, 0.5H), 3.79-3.92 (m, 1H), 3.65-3.79 (m,2.5H), 3.31 (br. s., 0.5H), 3.14 (d, J=12.0 Hz, 1H), 2.99-3.11 (m,1.5H), 2.58 (br. s., 2H), 2.17-2.26 (m, 3H), 1.90-2.00 (m, 2H),1.51-1.62 (m, 1H), 1.43 (d, J=10.3 Hz, 1H), 1.02-1.16 (m, 2H), 0.87 (dd,J=7.9, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.54 (br. s., 1H), 0.31-0.50 (m,2H)

LC-MS: m/z 472.5 (M+H)⁺

Compound 7812-cyclopropyl-6-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) 8.70 (d, J=5.0 Hz, 1H), 7.21-7.28 (m, 1H), 7.09(br. s., 1H), 6.89 (dd, J=17.3, 10.9 Hz, 1H), 6.30 (d, J=17.3 Hz, 1H),5.59 (d, J=10.9 Hz, 1H), 5.26-5.33 (m, 1H), 4.67-4.78 (m, 1.5H), 4.56(dt, J=9.1, 5.9 Hz, 1H), 4.38-4.48 (m, 1.5H), 4.29 (d, J=12.3 Hz, 1H),3.89 (d, J=13.5 Hz, 0.5H), 3.45-3.61 (m, 1H), 2.92-3.15 (m, 3.5H),2.78-2.91 (m, 2H), 2.44-2.65 (m, 1H), 2.26 (br. s., 0.5H), 2.19-2.23 (m,3H), 2.11-2.18 (m, 0.5H), 1.56 (td, J=8.0, 4.5 Hz, 1H), 1.12 (br. s.,1H), 1.04 (d, J=6.5 Hz, 4H), 0.93 (d, J=6.7 Hz, 1H), 0.83-0.90 (m, 4H)

LC-MS: m/z 486.6 (M+H)⁺

Compound 795(R,E)-2-cyclopropyl-6-(4-(5-hydroxypent-2-enoyl)-3-isopropylpiperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) 8.68 (d, J=5.0 Hz, 1H), 7.23 (d, J=9.7 Hz, 1H),7.07 (br. s., 1H), 6.81-6.94 (m, 2H), 6.40 (d, J=15.3 Hz, 1H), 6.28 (d,J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.35-4.52 (m, 1.5H), 4.28 (d,J=9.4 Hz, 1H), 3.94 (d, J=12.9 Hz, 0.5H), 3.80 (t, J=5.9 Hz, 2H), 3.68(d, J=9.7 Hz, 0.5H), 3.52 (t, J=11.9 Hz, 0.5H), 3.05-3.18 (m, 2H), 2.51(q, J=6.4 Hz, 2H), 2.25-2.32 (m, 1H), 2.20 (s, 3H), 2.05 (d, J=7.3 Hz,1H), 1.51-1.61 (m, 1H), 1.10 (br. s., 1H), 1.04 (d, J=6.5 Hz, 4H), 0.93(d, J=6.7 Hz, 1H), 0.76-0.95 (m, 4H)

LC-MS: m/z 486.6 (M+H)⁺

Compound 782(R)-6-(4-(2-cyclopentylacetyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) 8.69 (d, J=5.0 Hz, 1H), 7.24 (s, 1H), 7.08 (d,J=4.4 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.6 Hz, 1H),5.57 (d, J=10.9 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.0 Hz,1H), 4.13 (q, J=7.2 Hz, 1H), 3.70-3.91 (br. s., 1.5H), 3.23-3.39 (m,0.5H), 3.09-3.21 (m, 1H), 3.03 (t, J=10.7 Hz, 1H), 2.33-2.51 (m, 2H),2.24-2.32 (m, 1H), 2.17-2.24 (m, 3H), 1.80-1.95 (m, 2H), 1.61-1.72 (m,2H), 1.50-1.61 (m, 3H), 1.43 (d, J=12.6 Hz, 1H), 1.14-1.24 (m, 2H), 1.11(br. s., 2H), 0.82-0.91 (m, 2H), 0.51-0.75 (m, 2H), 0.44 (d, J=5.0 Hz,2H)

LC-MS: m/z 496.7 (M+H)⁺

COMPOUND 788(R)-2-cyclopropyl-6-(3-isopropyl-4-(4-methoxybutanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) 8.68 (d, J=5.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H),7.07 (br. s., 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.23-6.33 (m, 1H),5.48-5.66 (m, 1H), 4.69 (d, J=10.9 Hz, 0.5H), 4.37-4.48 (m, 1.5H),4.23-4.31 (m, 1H), 3.82 (d, J=13.8 Hz, 0.5H), 3.41-3.53 (m, 3H),3.22-3.38 (m, 3H), 2.92-3.15 (m, 3H), 2.39-2.56 (m, 2H), 2.25-2.33 (m,0.5H), 2.17-2.24 (m, 3H), 2.09-2.17 (m, 0.5H), 1.90-2.00 (m, 2H),1.52-1.60 (m, 1H), 1.09-1.15 (m, 1H), 1.03 (dd, J=6.5, 2.6 Hz, 4H), 0.91(d, J=6.7 Hz, 1H), 0.80-0.89 (m, 4H)

LC-MS: m/z 488.7 (M+H)⁺

Compound 787(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-cyclopropylacetyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) 8.71 (d, J=5.0 Hz, 1H), 7.26 (br. s., 1H), 7.09(d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.25 (d, J=17.6 Hz,1H), 5.57 (d, J=11.2 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.25 (d, J=12.6Hz, 1H), 4.04-4.16 (m, 0.5H), 3.68-3.86 (m, 1.5H), 3.16 (br. s., 1.5H),3.03 (br. s., 1H), 2.36 (br. s., 1.5H), 2.26 (d, J=7.3 Hz, 2H), 2.20 (s,3H), 1.50-1.59 (m, 1H), 1.05-1.11 (m, 3H), 0.86 (dd, J=7.9, 3.2 Hz, 2H),0.55-0.61 (m, 4H), 0.44 (br. s., 1H), 0.16-0.23 (m, 3H)

LC-MS: m/z 468.6 (M+H)⁺

Compound 4086-cyclopropyl-5-(isoquinolin-4-yl)-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.41 (br. s., 1H), 8.07-8.19 (m,1H), 7.65-7.76 (m, 2H), 7.46 (t, J=9.0 Hz, 1H), 4.96 (br. s., 0.5H),4.58 (br. s., 0.5H), 4.11-4.38 (m, 2.5H), 3.73-3.89 (m, 2.5H), 3.58-3.64(m, 0.5H), 3.41 (s, 3H), 3.04-3.32 (m, 2.5H), 2.56-2.84 (m, 2H), 2.10(s, 3H), 1.42-1.51 (m, 1H), 1.31-1.41 (m, 3H), 1.03-1.14 (m, 2H),0.63-0.83 (m, 2H)

LC-MS: m/z 470.4 (M+H)⁺

Compound 4106-cyclopropyl-5-(isoquinolin-5-yl)-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.48 (br. s., 1H), 8.58 (br. s., 1H), 8.13 (d,J=8.3 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.64 (d, J=7.0 Hz, 1H), 7.32 (d,J=10.3 Hz, 1H), 4.96 (br. s., 0.5H), 4.58 (d, J=12.3 Hz, 0.5H),4.08-4.36 (m, 2.5H), 3.71-3.93 (m, 2.5H), 3.56-3.70 (m, 0.5H), 3.41 (s,3H), 3.19-3.36 (m, 1.5H), 3.01-3.14 (m, 1H), 2.56-2.78 (m, 2H),2.02-2.10 (m, 3H), 1.81 (br. s., 1H), 1.42-1.50 (m, 3H), 1.05-1.15 (m,2H), 0.61-0.81 (m, 2H)

LC-MS: m/z 470.6 (M+H)⁺

Compound 470(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methylpyridin-3-yl)phenyl)ethenesulfonamide

¹H NMR (CHLOROFORM-d) δ 7.44 (t, J=7.8 Hz, 1H), 7.13-7.23 (m, 1H),6.96-7.12 (m, 2H), 6.48-6.67 (m, 2H), 6.32 (d, J=16.3 Hz, 1H), 6.02 (d,J=10.0 Hz, 1H), 4.58 (br. s., H), 4.34 (d, J=12.5 Hz, 1H), 4.26 (d,J=12.3 Hz, 1H), 3.76 (br. s., 2H), 3.23 (br. s., 1H), 3.07 (br. s., 1H),2.19 (s, 3H), 1.73 (br. s., 1H), 1.32 (d, J=11.5 Hz, 2H), 0.96-1.15 (m,4H), 0.74-0.88 (m, 4H), 0.67 (br. s., 1H), 0.37-0.60 (m, 3H)

LC-MS: m/z 532.7 (M+H)⁺

Compound 271(R)-5-(3-chloro-4-fluorophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.22-7.30 (m, 2H), 7.08 (ddd, J=8.2, 4.6, 2.0Hz, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.00-4.29 (m,2.5H), 3.66-3.85 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3H), 3.01-3.25(m, 2.5H), 2.63-2.84 (m, 1H), 2.48-2.63 (m, 1H), 2.18 (s, 3H), 1.51-1.61(m, 1H), 1.31-1.40 (m, 2H), 1.01-1.14 (m, 2H), 0.80-0.90 (m, 2H)

LC-MS: m/z 471.2 (M+H)⁺

Compound 5682-cyclopropyl-6-((3R)-3-cyclopropyl-4-(3-hydroxybutanoyl)piperazin-1-yl)-2′-vinyl-3,4′bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.39 (s,1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d,J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.43 (d,J=12.5 Hz, 1H), 4.17-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.79 (br. s., 1H),3.71 (d, J=11.8 Hz, 1H), 3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48(m, 1H), 2.04 (m, 1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br.s., 1H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H)

LC-MS: m/z 458.2 (M+H)⁺

Compound 558(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) δ 8.59 (d, J=4.8 Hz, 1H), 7.16 (s, 1H), 7.00 (d,J=4.8 Hz, 1H), 6.78 (dd, J=17.3, 10.8 Hz, 1H), 6.19 (d, J=17.6 Hz, 1H),5.46 (dd, J=10.8, 1.0 Hz, 1H), 4.60 (d, J=10.5 Hz, 0.5H), 4.26 (d,J=12.8 Hz, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.96-4.06 (m, 0.5H), 3.80 (d,J=12.3 Hz, 1H), 3.59-3.74 (m, 3H), 3.18-3.37 (m, 4H), 3.04-3.14 (m, 1H),2.90-3.01 (m, 1H), 2.37-2.67 (m, 2H), 2.08-2.18 (m, 3H), 1.39-1.56 (m,1H), 0.98-1.10 (m, 2H), 0.78 (dd, J=7.9, 3.1 Hz, 2H), 0.51 (br. s., 1H),0.44 (br. s., 1H), 0.29-0.40 (m, 2H)

LC-MS: m/z 472.4 (M+H)⁺

Compound 598(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-(prop-1-en-2-yl)pyrimidin-4-yl)nicotinonitrile

1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.98 (s, 1H), 7.61-7.76 (m, 1H),6.18 (s, 1H), 5.54 (s, 1H), 4.88 (br. s., 1H), 4.51 (d, J=9.8 Hz, 1H),4.18-4.47 (m, 3H), 3.63-3.93 (m, 3H), 3.41-3.63 (m, 1H), 3.36 (s, 4H),2.97-3.24 (m, 2H), 2.49-2.79 (m, 2H), 2.28-2.47 (m, 1H), 2.22 (s, 3H),1.34 (d, J=6.3 Hz, 2H), 1.14-1.30 (m, 4H), 1.04 (dd, J=7.9, 2.9 Hz, 2H)

LC-MS: m/z 447.2 (M+H)⁺

Compound 478(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-4-methyl-5-(1H-pyrazol-4-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.61 (s, 2H), 4.59 (s, 1H), 4.33 (d, J=12.5 Hz,1H), 4.24 (d, J=12.5 Hz, 1H), 3.98-4.15 (m, 1H), 3.84 (s, 1H), 3.22 (d,J=15.1 Hz, 1H), 3.05 (s, 1H), 2.31 (s, 3H), 1.83-1.98 (m, 1H), 1.73 (s,1H), 1.37-1.60 (m, 1H), 0.98-1.15 (m, 4H), 0.74-0.92 (m, 4H), 0.34-0.65(m, 4H).

LC-MS: m/z 416.2 (M+H)⁺

Compound 463(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methylpyridin-3-yl)phenyl)-N-(vinylsulfonyl)ethenesulfonamide

¹H NMR (CHLOROFORM-d) δ 7.47-7.60 (m, 1H), 7.31-7.40 (m, 2H), 7.00-7.14(m, 2H), 6.28 (s, 1H), 6.32 (s, 1H), 6.17 (d, J=9.8 Hz, 2H), 4.34 (d,J=12.8 Hz, 1H), 4.26 (d, J=12.5 Hz, 2H), 3.85 (s, 1H), 3.06 (br. s.,2H), 1.85 (br. s., 1H), 1.72 (br. s., 1H), 1.58 (td, J=8.2, 4.1 Hz, 2H),0.95-1.18 (m, 4H), 0.72-0.95 (m, 5H), 0.65 (br. s., 1H), 0.32-0.59 (m,3H)

LC-MS: m/z 622.2 (M+H)⁺

Compound 535(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)pyridin-3-yl)quinoline-2-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.27 (d, J=8.5 Hz, 1H), 8.11 (dd, J=11.5, 8.8Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.53-7.78 (m, 3H), 4.59 (dt, J=13.1,2.3 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 4.04-4.34 (m, 1H), 3.81 (br. s.,1H), 3.21-3.51 (m, 3H), 3.15 (d, J=11.5 Hz, 2H), 1.68 (br. s., 2H),1.37-1.48 (m, 3H), 1.14-1.36 (m, 13H), 0.77-1.04 (m, 4H), 0.71 (br. s.,1H), 0.60 (br. s., 1H), 0.31-0.57 (m, 2H)

LC-MS: m/z 513.2 (M+H)⁺

Compound 563(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinoline-2-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.25 (d, J=8.8 Hz, 1H), 8.13 (dd, J=10.3, 9.0Hz, 1H), 7.85-8.04 (m, 1H), 7.56-7.76 (m, 3H), 4.59 (d, J=12.0 Hz, 1H),4.47 (d, J=12.5 Hz, 2H), 4.13 (q, J=7.0 Hz, 1H), 3.72 (br. s., 1H), 3.42(d, J=10.0 Hz, 1H), 3.09-3.36 (m, 2H), 1.66-1.86 (m, 1H), 1.52-1.66 (m,1H), 1.36-1.52 (m, 2H), 1.00-1.30 (m, 8H), 0.75-1.00 (m, 6H), 0.71 (d,J=7.8 Hz, 1H), 0.34-0.63 (m, 4H)

LC-MS: m/z 489.2 (M+H)⁺

Compound 610(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(1-propioloyl-2,5-dihydro-1H-pyrrol-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) d: 7.53 (d, J=1.0 Hz, 1H), 6.00 (dt, J=19.1, 2.0Hz, 1H), 4.61-4.91 (m, 2H), 4.52-4.61 (m, 1H), 4.40-4.52 (m, 2H),4.19-4.40 (m, 2H), 3.50 (s, 1H), 3.43 (d, J=6.0 Hz, 1H), 3.02-3.32 (m,3H), 2.09-2.31 (m, 2H), 1.75 (br. s., 2H), 1.37-1.48 (m, 1H), 1.11-1.37(m, 7H), 0.95-1.11 (m, 2H), 0.66-0.95 (m, 2H).

LC-MS: m/z 430.2 (M+H)⁺

Compound 450(R)—N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)phenyl)propionamide

¹H NMR (CHLOROFORM-d) d: 7.70 (d, J=6.0 Hz, 2H), 7.61 (s, 1H), 7.48 (d,J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 4.50 (d,J=11.8 Hz, 1H), 4.38 (d, J=12.3 Hz, 1H), 3.73 (d, J=7.0 Hz, 1H), 3.25(br. s., 1H), 3.07 (br. s., 1H), 2.38-2.51 (m, 2H), 1.98-2.22 (m, 1H),1.73 (br. s., 1H), 1.21-1.45 (m, 6H), 1.16 (dt, J=7.8, 3.6 Hz, 3H),0.87-1.11 (m, 5H), 0.76-0.86 (m, 2H), 0.65 (br. s., 1H), 0.29-0.59 (m,3H).

LC-MS: m/z 484.3 (M+H)⁺

Compound 834 (General Procedure 2, Step M)6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile

¹H NMR (DEUTERIUM OXIDE) 9.35 (s, 1H), 8.54 (dd, J=5.9, 1.9 Hz, 1H),8.07 (d, J=8.0 Hz, 1H), 7.69-7.75 (m, 1H), 7.64-7.68 (m, 2H), 7.44 (dd,J=12.5, 6.0 Hz, 1H), 4.46-4.59 (m, 2.5H), 4.08-4.18 (m, 1H), 3.86 (br.s., 0.5H), 3.53-3.74 (m, 3H), 3.21-3.32 (m, 2H), 1.87-2.06 (m, 2H),1.49-1.58 (m, 1H), 1.33 (d, J=5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.81-0.90(m, 2H), 0.65 (br. s., 1H), 0.36-0.59 (m, 3H).

LC-MS: m/z 508.2 (M+H)⁺

COMPOUND 730(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(methyl(2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.25 (d, J=5.9 Hz, 1H), 7.58 (s, 1H), 6.71 (dd,J=17.4, 10.7 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.20 (d, J=17.3 Hz,1H), 5.45 (d, J=11.2 Hz, 1H), 4.69 (d, J=13.4 Hz, 0.4H), 4.49 (d, J=13.0Hz, 1H), 4.37 (d, J=12.7 Hz, 1H), 4.10 (d, J=8.6 Hz, 0.6H), 3.92 (s,2H), 3.86-3.65 (m, 1.5H), 3.42 (s, 1H), 3.31 (s, 3H), 3.22 (m, 1.5H),3.15-3.00 (m, 1H), 2.69-2.45 (m, 2H), 1.88 (ddd, J=12.7, 8.1, 4.7 Hz,1H), 1.40-1.31 (m, 1H), 1.12 (s, 2H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).

LC-MS: m/z 473.4 (M+H)⁺

Compound 835(R)-4-cyclopropyl-2-(3-cyclopropyl-4-(4-methoxybutanoyl)piperazin-1-yl)-5-(2-vinylpyridin-4-yl)benzonitrile

¹H NMR (CHLOROFORM-d) 8.64 (d, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.34-7.42(m, 1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz, 1H),6.54 (s, 1H), 6.21-6.33 (m, 1H), 5.55 (dd, J=10.9, 0.9 Hz, 1H),4.63-4.77 (m, 0.3H), 4.01-4.18 (m, 0.7H), 3.80-3.94 (m, 1H), 3.41-3.82(m, 4H), 3.35 (s, 3H), 3.18-3.35 (m, 1H), 2.97-3.05 (m, 1H), 2.79-2.93(m, 1H), 2.46 (d, J=7.3 Hz, 2H), 1.81-1.99 (m, 4H), 0.94-1.07 (m, 2H),0.72-0.83 (m, 2H), 0.36-0.56 (m, 4H).

LC-MS: m/z 471.2 (M+H)⁺

Compound 775(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-((5-vinylpyridazin-3-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 7.76 (s, 1H), 6.58 (dd, J=17.6,11.0 Hz, 2H), 6.05 (d, J=17.6 Hz, 1H), 5.66 (d, J=11.0 Hz, 1H),4.65-4.70 (m, 0.5H), 4.43-4.46 (m, 1H), 4.33 (d, J=12.4 Hz, 1H),4.16-4.07 (m, 1H), 3.87-3.88 (m, 0.5H), 3.71-3.74 (m, 3H), 3.39 (s, 3H),3.20 (s, 1H), 3.07-3.09 (m, 1H), 2.65-2.66 (m, 2H), 2.55-2.47 (m, 1H),2.18 (d, J=10.1 Hz, 1H), 1.30-1.25 (m, 1H), 1.15 (s, 2H), 1.07-0.98 (m,2H), 0.50-0.60 (m, 2H), 0.45-0.47 (m, 2H).

LC-MS: m/z 474.6 (M+H)⁺

Compound 836(R)-tert-butyl(5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)pyridin-3-yl)pyridazin-3-yl)carbamate

The mixture of(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(268 mg, 0.627 mmol), tert-butyl (5-chloropyridazin-3-yl)carbamate (120mg, 0.523 mmol), Pd(dppf)Cl₂ (20 mg, 0.026 mmol) and CsF (159 mg, 1.045mmol) in dioxane/H₂O (8 mL/2 mL) was stirred at 100° C. for 16 hours.The mixture was diluted with EtOAc (50 mL) and filtered. The filtratedwas partitioned between EtOAc (50 mL) and water (30 mL), the organiclayer was washed with water (30 mL), brine and dried over Na₂SO₄ andconcentrated to give the crude which was purified by prep-TLC to give150 mg of the product.

¹H NMR (CHLOROFORM-d): 8.97 (d, J=2.1 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H),8.24 (br. s., 1H), 7.70 (s, 1H), 4.62 (d, J=13.2 Hz, 1H), 4.49 (d,J=12.9 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 3.92 (t, J=4.5 Hz, 2H),3.63-3.85 (m, 1H), 3.02-3.23 (m, 3H), 2.41-2.67 (m, 2H), 1.91-2.06 (m,1H), 1.48-1.63 (m, 9H), 1.15-1.25 (m, 3H), 1.02-1.13 (m, 2H), 0.46-0.72(m, 4H)

LC-MS: m/z 534.3 (M+H)⁺

Compound 339 (General Procedure 9)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(quinolin-3-ylamino)nicotinonitrile

¹H NMR (MeOD): δ 8.797-8.790 (d, J=2.8 Hz, 1H), 8.059-8.037 (d, J=8.8Hz, 1H), 7.985-7.962 (d, J=9.2 Hz, 1H), 7.926-7.920 (d, J=2.4 Hz, 1H),7.861 (s, 1H), 7.795-7.710 (m, 2H), 4.797-4.783 (m, 0.5H), 4.451-4.416(m, 1H), 4.227-4.112 (m, 2H), 3.972-3.932 (m, 0.5H), 3.694-3.613 (m,2H), 3.608-3.577 (m, 0.5H), 3.334 (s, 3H), 3.284 (m, 0.5H), 3.211-3.137(m, 1H), 3.045-3.007 (m, 0.5H), 2.852-2.704 (m, 1H), 2.700-2.578 (m,1.5H), 2.240-2.177 (m, 1H), 1.401-1.384 (d, J=6.8 Hz, 1.5H), 1.284-1.267(d, J=6.8 Hz, 1.5H), 1.188-1.170 (m, 2H), 0.992-0.965 (m, 2H);

LC-MS: m/z 471.5 (M+H)⁺

Compound 355 (General Procedure 9)(R)-6-cyclopropyl-5-((4-fluorophenyl)amino)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

1H NMR (MeOD): δ 7.543 (s, 1H), 6.936-6.893 (t, J=8.6 Hz, 2H),6.723-6.690 (q, J=4.4 Hz, 2H), 4.798-4.781 (m, 0.5H), 4.443-4.361 (m,1H), 4.050-3.898 (m, 2.5H), 3.675-3.509 (m, 2.5H), 3.336 (s, 3H),3.254-2.877 (m, 2.5H), 2.792-2.588 (m, 2H), 2.260-2.196 (m, 1H),1.402-1.255 (m, 3H), 1.115-1.097 (m, 2H), 0.992-0.968 (m, 2H);

LC-MS: m/z 438.5 (M+H)⁺

Compound 356 (General Procedure 9)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(quinolin-4-ylamino)nicotinonitrile

¹H NMR (MeOD): δ 8.593-8.572 (d, J=8.4 Hz, 1H), 8.440-8.422 (d, J=7.2Hz, 1H), 8.065-8.026 (m, 1H), 7.983-7.962 (d, J=8.4 Hz, 1H), 7.931 (s,1H), 7.854-7.813 (m, 2H), 6.552-6.535 (d, J=6.8 Hz, 1H), 4.792-4.783 (m,0.5H), 4.451-4.420 (m, 1H), 4.329-4.207 (m, 2H), 3.982-3.948 (m, 0.5H),3.414-3.338 (m, 4H), 3.257-3.068 (m, 1.5H), 2.829-2.610 (m, 2H),2.091-2.026 (m, 1H), 1.389-1.256 (m, 3H), 1.199-1.181 (m, 2H),1.050-0.988 (m, 2H);

LC-MS: m/z 471.5 (M+H)⁺

Compound 368 (General Procedure 9)(R)-5-(4-acetylpiperazin-1-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

1H NMR (MeOD): δ 7.558 (s, 1H), 4.763-4.752 (m, 0.5H), 4.429-4.346 (m,1H), 4.052-3.883 (m, 3H), 3.747-3.668 (m, 6H), 3.328 (s, 3H),3.182-3.119 (m, 2H), 3.061-2.886 (m, 4.5H), 2.781-2.677 (m, 1H),2.623-2.562 (m, 2H), 2.142 (s, 3H), 1.375-1.358 (m, 1.5H), 1.261-1.244(m, 1.5H), 1.109-1.036 (m, 4H);

LC-MS: m/z 455.5 (M+H)⁺

Compound 375 (General Procedure 9)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-morpholinonicotinonitrile

¹H NMR (MeOD): δ 7.551 (s, 1H), 4.762-4.748 (m, 0.5H), 4.428-4.352 (m,1H), 4.039-3.975 (m, 2H), 3.941-3.827 (m, 5H), 3.681-3.667 (m, 2H),3.574-3.501 (m, 1H), 3.327 (s, 3H), 3.173-3.116 (m, 2H), 3.046-2.991 (m,1H), 2.940-2.882 (m, 4H), 2.744-2.522 (m, 2.5H), 1.378-1.361 (m, 1.5H),1.264-1.247 (m, 1.5H), 1.097-1.012 (m, 4H);

LC-MS: m/z 414.5 (M+H)⁺

Compound 376 (General Procedure 9) (R)-ethyl4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)piperazine-1-carboxylate

1H NMR (MeOD): δ 7.549 (s, 1H), 4.763-4.747 (m, 0.5H), 4.426-4.343 (m,1H), 4.171-4.118 (m, 2H), 4.044-3.882 (m, 1.5H), 3.666-3.639 (m, 6H),3.573-3.501 (m, 1H), 3.327 (s, 3H), 3.176-2.988 (m, 2H), 2.911-2.886 (m,4.5H), 2.781-2.546 (m, 3H), 1.374-1.358 (m, 1.5H), 1.289-1.253 (m,4.5H), 1.101-1.026 (m, 4H);

LC-MS: m/z 485.6 (M+H)⁺

Compound 377 (General Procedure 9)(R)-6-cyclopropyl-5-(4-(ethylsulfonyl)piperazin-1-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

1H NMR (MeOD): δ 7.587 (s, 1H), 4.765-4.749 (m, 0.5H), 4.426-4.348 (m,1H), 4.055-3.882 (m, 1.5H), 3.669-3.457 (m, 7H), 3.329 (s, 3H),3.152-3.066 (m, 4H), 3.004-2.888 (m, 4.5H), 2.742-2.538 (m, 3H),1.373-1.335 (m, 4.5H), 1.261-1.245 (m, 1.5H), 1.094-1.036 (m, 4H);

LC-MS: m/z 505.6 (M+H)⁺

Compound 378 (General Procedure 9)(R)-6-cyclopropyl-5-(4-(cyclopropylmethyl)piperazin-1-yl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

1H NMR (MeOD): δ 7.598 (s, 1H), 4.768-4.752 (m, 0.5H), 4.431-4.355 (m,1H), 4.068-3.892 (m, 2.5H), 3.688-3.660 (m, 2H), 3.572-3.507 (m, 1H),3.333 (s, 3H), 3.101-2.930 (m, 9H), 2.903-2.871 (m, 1H), 2.787-2.586 (m,4H), 2.544-2.493 (m, 1H), 1.378-1.362 (m, 1.5H), 1.264-1.248 (m, 1.5H),1.124-1.044 (m, 5H), 0.698-0.652 (m, 2H), 0.357-0.268 (m, 2H);

LC-MS: m/z 467.6 (M+H)⁺

Compound 379 (General Procedure 9)(R)-5-(4-benzoylpiperazin-1-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

1H NMR (MeOD): δ 7.588 (s, 1H), 7.492-7.451 (m, 5H), 4.780-4.768 (m,0.5H), 4.430-4.346 (m, 1H), 4.053-3.881 (m, 4.5H), 3.667-3.630 (m,2.5H), 3.536-3.477 (m, 2H), 3.326 (m, 4H), 3.180-3.085 (m, 1.5H),3.023-2.923 (m, 5H), 2.756-2.709 (m, 1H), 2.619-2.567 (m, 2H),1.373-1.357 (m, 1.5H), 1.259-1.243 (m, 1.5H), 1.113-1.033 (m, 4H);

LC-MS: m/z 517.6 (M+H)⁺

Compound 265 (General Procedure 6)(R)-6-cyclopropyl-5-(3-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.41-7.51 (m, 1H), 7.12 (td, J=8.5, 2.5 Hz, 1H),7.01 (d, J=7.5 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.92 (br. s., 0.5H),4.55 (d, J=12.8 Hz, 0.5H), 4.02-4.22 (m, 2.5H), 3.70-3.92 (m, 2.5H),3.53-3.67 (m, 0.5H), 3.40 (s, 3H), 2.92-3.31 (m, 2.5H), 2.61-2.84 (m,21H), 2.16-2.25 (m, 3H), 1.57-1.65 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H),1.33 (d, J=6.8 Hz, 1.5H), 1.08 (t, J=4.6 Hz, 2H), 0.79-0.90 (m, 2H)

LC-MS: m/z 437.4 (M+H)⁺

Compound 264 (General Procedure 6)6-cyclopropyl-5-(2,4-difluorophenyl)-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.15-7.25 (m, 1H), 6.94-7.06 (m, 2H), 4.92 (br.s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.05-4.34 (m, 2.5H), 3.70-3.85 (m,2.5H), 3.52-3.67 (m, 0.5H), 3.40 (s, 3H), 2.93-3.31 (m, 2.5H), 2.73 (td,J=15.3, 7.3 Hz, 1H), 2.54-2.64 (m, 1H), 2.21 (s, 3H), 1.54-1.61 (m, 1H),1.39-1.45 (m, 1.5H), 1.32 (t, J=5.8 Hz, 1.5H), 1.01-1.18 (m, 2H),0.83-0.93 (m, 2H)

LC-MS: m/z 455.4 (M+H)⁺

Compound 263 (General Procedure 6)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(4-(trifluoromethoxy)phenyl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.31-7.36 (m, J=8.0 Hz, 2H), 7.23-7.28 (m, J=8.3Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.8 Hz, 0.5H), 4.00-4.22 (m,2.5H), 3.68-3.87 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.36-3.44 (m, 3H),3.12-3.31 (m, 1.5H), 2.94-3.12 (m, 1H), 2.64-2.83 (m, 1H), 2.61 (br. s.,1H), 2.16-2.22 (m, 3H), 1.52-1.63 (m, 1H), 1.39-1.47 (m, 1.5H), 1.32 (d,J=6.3 Hz, 1.5H), 1.03-1.15 (m, 2H), 0.78-0.90 (m, 2H)

LC-MS: m/z 503.3 (M+H)⁺

Compound 272 (General Procedure 8) (R)-benzyl2-(5-cyano-2-isopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)ethylcarbamate

¹H NMR (CHLOROFORM-d) δ 7.32-7.40 (m, 5H), 7.18 (s, 1H), 4.90 (br. s.,0.5H), 4.53 (d, J=12.5 Hz, 0.5H), 4.21 (br. s., 0.5H), 4.06 (d, J=14.1Hz, 1H), 3.95-4.01 (m, 2.5H), 3.68-3.79 (m, 3H), 3.53-3.67 (m, 2.5H),3.30-3.44 (m, 5H), 3.07-3.25 (m, 2H), 2.89-3.07 (m, 1H), 2.51-2.79 (m,2.5H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.11-1.20 (m,7H)

LC-MS: m/z 524.3 (M+H)⁺

Compound 270 (General Procedure 6)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(thiophen-3-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.47 (dd, J=5.0, 3.0 Hz, 1H), 7.17 (dd, J=2.8,1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H), 4.91 (br. s., 0.5H), 4.55 (d,J=10.8 Hz, 0.5H), 3.98-4.28 (m, 2.5H), 3.75 (q, J=6.0 Hz, 2.5H),3.50-3.67 (m, 0.5H), 3.36-3.46 (m, 3H), 3.10-3.30 (m, 1.5H), 2.89-3.10(m, 1H), 2.65-2.81 (m, 2H), 2.25 (s, 3H), 1.71-1.79 (m, 1H), 1.42 (d,J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.05-1.12 (m, 2H), 0.81-0.90(m, 2H)

LC-MS: m/z 425.3 (M+H)⁺

Compound 269 (General Procedure 6)(R)-5-(benzo[d][1,3]dioxol-5-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 6.91 (d, J=8.0 Hz, 1H), 6.60-6.74 (m, 2H),6.01-6.11 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.6 Hz, 0.5H), 4.24(br. s., 0.5H), 4.02-4.20 (m, 2H), 3.70-3.85 (m, 2.5H), 3.59 (t, J=11.7Hz, 0.5H), 3.39 (s, 3H), 3.19 (t, J=13.7 Hz, 1.5H), 2.92-3.08 (m, 1H),2.65-2.83 (m, 1H), 2.55-2.64 (m, 1H), 2.19-2.27 (m, 3H), 1.67-1.76 (m,1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.31-1.38 (m, 1.5H), 1.06 (t, J=5.3 Hz,2H), 0.79-0.91 (m, 2H)

LC-MS: m/z 463.3 (M+H)⁺

Compound 268 (General Procedure 6)(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.87 (br. s., 2H), 7.86 (br. s., 2H), 4.90-5.00(m, 0.5H), 4.57 (br. s., 0.5H), 4.33 (d, J=12.5 Hz, 2.5H), 3.71-3.82 (m,2.5H), 3.58 (br. s., 0.5H), 3.40 (s, 3H), 3.09-3.28 (m, 2.5H), 2.68 (br.s., 1H), 2.61 (br. s., 1H), 2.23-2.28 (m, 3H), 1.62-1.66 (m, 1H),1.32-1.38 (m, 3H), 1.20 (br. s., 2H), 0.98 (br. s., 2H)

LC-MS: m/z 420.5 (M+H)⁺

Compound 267 (General Procedure 6)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methyl-5-(naphthalen-2-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.84-8.00 (m, 3H), 7.71 (s, 1H), 7.53-7.60 (m,2H), 7.34 (dd, J=8.4, 1.4 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d, J=13.3Hz, 0.5H), 4.06-4.34 (m, 2.5H), 3.71-3.85 (m, 2.5H), 3.52-3.69 (m,0.5H), 3.37-3.45 (m, 3H), 3.14-3.30 (m, 1.5H), 2.94-3.12 (m, 1H),2.67-2.85 (m, 1H), 2.54-2.66 (m, 1H), 2.19-2.28 (m, 3H), 1.62-1.70 (m,1H), 1.45 (d, J=5.8 Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.03-1.16 (m,2H), 0.74-0.84 (m, 2H)

LC-MS: m/z 469.4 (M+H)⁺

Compound 559 (General Procedure 9)(R)-6-cyclopropyl-5-(4-(ethylsulfonyl)piperazin-1-yl)-2-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.38 (s, 1H), 4.29 (d, J=12.8 Hz, 1H), 4.18 (d,J=12.5 Hz, 1H), 4.09 (d, J=7.5 Hz, 0.5H), 3.70-3.81 (m, 1.5H), 3.46-3.55(m, 4.5H), 3.30 (q, J=9.8 Hz, 2H), 2.92-3.14 (m, 8.5H), 2.38-2.53 (m,1H), 1.38-1.49 (m, 3H), 1.29-1.36 (m, 1H), 1.02-1.17 (m, 4H), 0.42-0.67(m, 4H)

LC-MS: m/z 555.2 (M+H)⁺

Compound 529 (General Procedure 9)(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(4-(ethylsulfonyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.37 (s, 1H), 3.42-4.57 (m, 9H), 2.90-3.22 (m,8H), 2.40-2.52 (m, 1H), 1.73 (br. s., 1H), 1.39-1.50 (m, 4H), 1.10-1.17(m, 2H), 0.95-1.09 (m, 4H), 0.76-0.85 (m, 2H), 0.35-0.58 (m, 4H)

LC-MS: m/z 513.2 (M+H)⁺

Compound 528 (General Procedure 9)(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(quinolin-4-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.55 (d, J=5.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H),8.10 (d, J=8.3 Hz, 1H), 7.67-7.78 (m, 2H), 7.51-7.63 (m, 1H), 6.32 (d,J=5.3 Hz, 1H), 4.50 (d, J=12.3 Hz, 1H), 4.38 (d, J=12.3 Hz, 1H),3.12-4.18 (m, 5H), 2.05-2.13 (m, 1H), 1.03-1.22 (m, 5H), 0.95-1.01 (m,3H), 0.83 (dd, J=7.9, 2.4 Hz, 2H), 0.39-0.62 (m, 4H)

LC-MS: m/z 479.3 (M+H)⁺

Compound 722 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-((2-vinyl-1,7-naphthyridin-4-yl)amino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 9.48 (s, 1H), 8.58 (d, J=5.9 Hz, 1H), 7.87 (br.s., 1H), 7.74 (s, 1H), 6.91 (dd, J=17.6, 10.9 Hz, 1H), 6.57 (s, 1H),6.27 (d, J=17.6 Hz, 1H), 5.69 (d, J=10.9 Hz, 1H), 4.52 (d, J=12.9 Hz,1H), 4.40 (d, J=12.3 Hz, 1H), 4.11 (d, J=7.9 Hz, 1H), 3.94 (br. s., 2H),3.64-3.88 (m, 1H), 3.33 (br. s., 1H), 3.24 (d, J=13.5 Hz, 1H), 3.03-3.19(m, 1H), 2.48-2.69 (m, 2H), 1.98-2.09 (m, 1H), 1.37 (d, J=16.1 Hz, 1H),1.10-1.22 (m, 2H), 0.95-1.08 (m, 2H), 0.66 (br. s., 1H), 0.57 (br. s.,1H), 0.49 (br. s., 2H)

LC-MS: m/z 430.2 (M+H)⁺

Compound 819 (General Procedure 6)(R)-6-(4-(2-cyclobutylacetyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) δ 8.69 (d, J=4.7 Hz, 1H), 7.23 (br. s., 1H), 7.07(d, J=4.4 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.3 Hz,1H), 5.57 (d, J=11.7 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.25 (d, J=12.0Hz, 1H), 4.09 (br. s., 1H), 3.80 (br. s., 1H), 3.13 (br. s., 2H), 3.02(br. s., 1H), 2.73 (dt, J=15.6, 7.8 Hz, 1H), 2.51 (br. s., 2H), 2.21 (s,3H), 2.10-2.20 (m, 2H), 1.67-1.97 (m, 5H), 1.50-1.66 (m, 1H), 1.43 (d,J=15.8 Hz, 1H), 1.11 (br. s., 2H), 0.83-0.93 (m, 2H), 0.61 (br. s., 1H),0.52 (br. s., 1H), 0.31-0.48 (m, 2H)

LC-MS: m/z 482.6 (M+H)⁺

Compound 820 (General Procedure 6)(R)-6-(4-(2-cyclobutylideneacetyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

1H NMR (CHLOROFORM-d) δ 8.70 (d, J=5.0 Hz, 1H), 7.25 (s, 1H), 7.09 (d,J=3.8 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.31 (d, J=17.3 Hz, 1H),5.92 (br. s., 1H), 5.59 (d, J=11.2 Hz, 1H), 4.35 (d, J=12.9 Hz, 1H),4.27 (d, J=12.6 Hz, 1H), 3.91-4.19 (m, 1H), 3.78 (br. s., 1H), 3.10-3.31(m, 3H), 3.04 (td, J=12.4, 3.4 Hz, 1H), 2.84 (t, J=8.4 Hz, 2H),2.43-2.55 (m, 1H), 2.22 (s, 3H), 1.98-2.17 (m, 2H), 1.53-1.63 (m, 1H),1.45 (br. s., 1H), 1.04-1.18 (m, 2H), 0.82-0.96 (m, 2H), 0.64 (br. s.,1H), 0.50 (br. s., 1H), 0.31-0.48 (m, 2H)

LC-MS: m/z 480.6 (M+H)⁺

Compound 266 (General Procedure 6)(R)-6-cyclopropyl-5-(3-fluoro-4-methylphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.25-7.31 (m, 1H), 6.85-6.92 (m, 2H), 4.91 (br.s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.00-4.23 (m, 2.5H), 3.68-3.87 (m,2.5H), 3.51-3.63 (m, 0.5H), 3.39 (s, 3H), 3.10-3.27 (m, 1.5H), 2.94-3.09(m, 1H), 2.64-2.82 (m, 1H), 2.55-2.64 (m, 1H), 2.32-2.39 (m, 3H), 2.20(s, 3H), 1.60-1.70 (m, 1H), 1.39-1.47 (m, 1.5H), 1.30-1.35 (m, 1.5H),1.07 (t, J=4.6 Hz, 2H), 0.83 (dt, J=7.5, 3.5 Hz, 2H)

LC-MS: m/z 451.4 (M+H)⁺

Compound 277 (General Procedure 8)6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(1-phenylethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.28-7.42 (m, 5H), 6.97 (d, J=3.3 Hz, 1H), 5.15(q, J=6.3 Hz, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=13.1 Hz, 0.5H), 4.15(br. s., 0.5H), 3.76-3.94 (m, 2H), 3.64-3.76 (m, 2.5H), 3.41-3.57 (m,0.5H), 3.36 (s, 3H), 2.96-3.13 (m, 1.5H), 2.77-2.96 (m, 1H), 2.61-2.77(m, 1H), 2.48-2.61 (m, 2H), 1.67 (d, J=6.3 Hz, 3H), 1.26 (d, J=5.3 Hz,3H), 0.97-1.15 (m, 4H)

LC-MS: m/z 449.2 (M+H)⁺

Compound 279 (General Procedure 8)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyridin-2-ylmethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.64 (d, J=4.5 Hz, 1H), 7.82 (t, J=7.3 Hz, 1H),7.51-7.62 (m, 1H), 7.29-7.39 (m, 1H), 7.23 (s, 1H), 5.22 (s, 2H), 4.88(br. s., 0.5H), 4.51 (d, J=12.8 Hz, 0.5H), 4.18 (br. s., 0.5H),3.82-4.03 (m, 2H), 3.63-3.81 (m, 2.5H), 3.44-3.61 (m, 0.5H), 3.37 (s,3H), 3.09 (t, J=13.2 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62-2.79 (m, 1H),2.45-2.61 (m, 2H), 1.26 (d, J=5.3 Hz, 3H), 0.99-1.16 (m, 4H)

LC-MS: m/z 436.2 (M+H)⁺

Compound 280 (General Procedure 8)(R)-6-cyclopropyl-5-(3-methoxybenzyloxy)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.32 (t, J=7.9 Hz, 1H), 7.18 (s, 1H), 6.93-7.05(m, 2H), 6.89 (dd, J=8.0, 2.3 Hz, 1H), 5.02 (s, 2H), 4.87 (br. s.,0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.92 (t, J=12.7Hz, 2H), 3.83 (s, 3H), 3.73 (t, J=6.1 Hz, 2.5H), 3.53 (d, J=8.0 Hz,0.5H), 3.37 (s, 3H), 3.01-3.18 (m, 1.5H), 2.81-3.00 (m, 1H), 2.62-2.78(m, 1H), 2.45-2.62 (m, 2H), 1.27-1.44 (m, 3H), 0.97-1.15 (m, 4H)

LC-MS: m/z 465.2 (M+H)⁺

Compound 281 (General Procedure 8)(R)-6-cyclopropyl-5-(4-methoxybenzyloxy)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.28-7.39 (m, J=8.8 Hz, 2H), 7.20 (s, 1H),6.88-6.97 (m, J=8.8 Hz, 2H), 4.96 (s, 2H), 4.88 (d, J=7.8 Hz, 0.5H),4.51 (d, J=13.3 Hz, 0.5H), 4.18 (br. s., 1H), 3.92 (t, J=12.5 Hz, 2H),3.83 (s, 3H), 3.67-3.78 (m, 2.5H), 3.46-3.60 (m, 0.5H), 3.37 (s, 3H),3.00-3.16 (m, 1.5H), 2.80-2.99 (m, 1H), 2.61-2.80 (m, 1H), 2.42-2.61 (m,2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 0.92-1.14 (m,4H)

LC-MS: m/z 465.2 (M+H)⁺

Compound 292 (General Procedure 8) (R)-methyl3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)methyl)benzoate

¹H NMR (CHLOROFORM-d) δ 8.11 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.63 (d,J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.19 (s, 1H), 5.07 (s, 2H), 4.88(br. s., 0.5H), 4.51 (d, J=13.6 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.94 (s,3H), 3.83-4.02 (m, 2H), 3.64-3.80 (m, 2.5H), 3.52 (br. s., 0.5H), 3.37(s, 3H), 3.09 (t, J=13.6 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62-2.80 (m,1H), 2.41-2.62 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz,1.5H), 0.98-1.15 (m, 4H)

LC-MS: m/z 493.2 (M+H)⁺

Compound 293 (General Procedure 8) (R)-methyl4-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)methyl)benzoate

¹H NMR (CHLOROFORM-d) δ 8.01-8.14 (m, 2H), 7.44-7.56 (m, J=8.5 Hz, 2H),7.18 (s, 1H), 5.10 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=13.6 Hz,0.5H), 4.19 (br. s., 0.5H), 3.93 (s, 3H), 3.82-4.02 (m, 2H), 3.66-3.81(m, 2.5H), 3.46-3.60 (m, 0.5H), 3.37 (s, 3H), 3.10 (t, J=13.7 Hz, 1.5H),2.82-3.01 (m, 1H), 2.62-2.79 (m, 1H), 2.43-2.62 (m, 2H), 1.39 (d, J=6.5Hz, 1.5H), 1.27-1.34 (m, 1.5H), 0.96-1.17 (m, 4H)

LC-MS: m/z 493.2 (M+H)⁺

Compound 294 (General Procedure 8)(R)-5-(3-cyanobenzyloxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.61-7.71 (m, 2H), 7.54 (t, J=7.9Hz, 1H), 7.17 (s, 1H), 5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.52 (d,J=13.6 Hz, 0.5H), 4.21 (br. s., 0.5H), 3.85-4.06 (m, 2H), 3.74 (br. s.,2.5H), 3.54 (br. s., 0.5H), 3.37 (s, 3H), 3.04-3.21 (m, 1.5H), 2.84-3.04(m, 1H), 2.55-2.81 (m, 2H), 2.40-2.51 (m, 1H), 1.39 (d, J=5.5 Hz, 1.5H),1.30 (d, J=6.3 Hz, 1.5H), 0.98-1.16 (m, 4H)

LC-MS: m/z 460.2 (M+H)⁺

Compound 301 (General Procedure 8)(R)-6-cyclopropyl-5-(4-(hydroxymethyl)benzyloxy)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.35-7.49 (m, 4H), 7.18 (s, 5.04 (s, 2H),4.81-4.91 (m, 0.5H), 4.73 (s, 2H), 4.50 (d, J=13.3 Hz, 0.5H), 4.18 (br.s., 0.5H), 3.81-4.00 (m, 2H), 3.64-3.81 (m, 2.5H), 3.45-3.60 (m, 0.5H),3.37 (s, 3H), 3.00-3.17 (m, 1.5H), 2.81-2.99 (m, 1H), 2.61-2.79 (m, 1H),2.43-2.61 (m, 2H), 1.92-2.08 (m, 1H), 1.31-1.41 (m, 3H), 0.97-1.14 (m,4H)

LC-MS: m/z 465.2 (M+H)⁺

Compound 302 (General Procedure 8)6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-methyl-1-phenylpropoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.27-7.39 (m, 5H), 6.87 (d, J=1.5 Hz, 1H), 4.84(br. s., 0.5H), 4.66-4.74 (m, 1H), 4.47 (d, J=13.3 Hz, 0.5H), 4.14 (br.s., 0.5H), 3.63-3.90 (m, 4.5H), 3.40-3.57 (m, 0.5H), 3.35 (s, 3H),2.93-3.12 (m, 1.5H), 2.76-2.93 (m, 1H), 2.47-2.75 (m, 3H), 2.18 (dq,J=13.3, 6.6 Hz, 1H), 1.19-1.39 (m, 3H), 1.00-1.11 (m, 7H), 0.87-0.97 (m,3H)

LC-MS: m/z 477.2 (M+H)⁺

Compound 303 (General Procedure 8)6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((S)-1-phenylethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.27-7.42 (m, 5H), 6.91-7.00 (m, 1H), 5.15 (q,J=6.5 Hz, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=13.6 Hz, 0.5H), 4.15 (br.s., 0.5H), 3.78-3.95 (m, 2H), 3.61-3.77 (m, 2.5H), 3.43-3.57 (m, 0.5H),3.36 (s, 3H), 2.96-3.13 (m, 1.5H), 2.85 (td, J=12.4, 2.8 Hz, 1H),2.48-2.76 (m, 3H), 1.67 (d, J=6.5 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H),1.21-1.28 (m, 1.5H), 0.97-1.13 (m, 4H)

LC-MS: m/z 449.2 (M+H)⁺

Compound 304 (General Procedure 8)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyridin-3-ylmethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.70 (s, 1H), 8.63 (d, J=3.8 Hz, 1H), 7.79 (dt,J=7.8, 1.9 Hz, 1H), 7.37 (dd, J=7.8, 4.8 Hz, 1H), 7.24 (s, 1H), 5.06 (s,2H), 4.88 (br. s., 0.5H), 4.51 (d, J=12.5 Hz, 0.5H), 4.20 (br. s.,0.5H), 3.83-4.04 (m, 2H), 3.63-3.83 (m, 2.5H), 3.53 (br. s., 0.5H), 3.37(s, 3H), 3.03-3.17 (m, 1.5H), 2.84-3.02 (m, 1H), 2.62-2.78 (m, 1H),2.51-2.62 (m, 1H), 2.39-2.51 (m, 1H), 1.36-1.43 (m, 2H), 1.27-1.34 (m,2H), 0.91-1.15 (m, 4H)

LC-MS: m/z 436.2 (M+H)⁺

Compound 307 (General Procedure 8)6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((R)-1-phenylethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.27-7.42 (m, 5H), 6.92-6.98 (m, 1H), 5.15 (q,J=6.4 Hz, 1H), 4.84 (br. s., 0.5H), 4.49 (d, J=13.6 Hz, 0.5H), 4.15 (br.s., 0.5H), 3.77-3.95 (m, 2H), 3.72 (t, J=6.3 Hz, 2.5H), 3.43-3.56 (m,0.5H), 3.36 (s, 3H), 2.97-3.13 (m, 1.5H), 2.78-2.95 (m, 1H), 2.48-2.78(m, 3H), 1.67 (d, J=6.3 Hz, 3H), 1.36 (d, J=6.8 Hz, 1.5H), 1.26 (d,J=5.5 Hz, 1.5H), 0.97-1.14 (m, 4H)

LC-MS: m/z 449.2 (M+H)⁺

Compound 308 (General Procedure 8)6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(1-phenylpropoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.28-7.42 (m, 5H), 6.92 (d, J=2.3 Hz, 1H),4.78-4.95 (m, 1.5H), 4.48 (d, J=13.3 Hz, 0.5H), 4.14 (br. s., 0.5H),3.77-3.93 (m, 2H), 3.65-3.77 (m, 2.5H), 3.48 (br. s., 0.5H), 3.36 (s,3H), 2.95-3.12 (m, 1.5H), 2.76-2.95 (m, 1H), 2.46-2.76 (m, 3H),2.00-2.13 (m, 1H), 1.84-1.98 (m, 1H), 1.36 (d, J=6.8 Hz, 1.5H),1.25-1.29 (m, 1.5H), 0.92-1.12 (m, 7H)

LC-MS: m/z 463.2 (M+H)⁺

Compound 309 (General Procedure 8)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyridin-4-ylmethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.67 (d, J=5.8 Hz, 2H), 7.39 (d, J=5.8 Hz, 2H),7.17 (s, 1H), 5.07 (s, 2H), 4.79-4.95 (m, 0.5H), 4.51 (d, J=13.6 Hz,0.5H), 4.19 (br. s., 0.5H), 3.86-4.04 (m, 2H), 3.62-3.81 (m, 2.5H),3.45-3.59 (m, 0.5H), 3.37 (s, 3H), 3.03-3.18 (m, 1.5H), 2.83-3.02 (m,1H), 2.62-2.79 (m, 1H), 2.43-2.61 (m, 2H), 1.39 (d, J=6.8 Hz, 1.5H),1.27-1.31 (m, 1.5H), 0.99-1.15 (m, 4H)

LC-MS: m/z 436.2 (M+H)⁺

Compound 310 (General Procedure 8)5-(1-(3-chlorophenyl)ethoxy)-6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.33-7.38 (m, 1H), 7.27-7.33 (m, 3H), 7.19-7.25(m, 1H), 6.96 (d, J=4.5 Hz, 1H), 5.11 (q, J=6.3 Hz, 1H), 4.85 (br. s.,0.5H), 4.49 (d, J=13.6 Hz, 0.5H), 4.16 (br. s., 0.5H), 3.78-3.97 (m,2H), 3.63-3.78 (m, 2.5H), 3.49 (br. s., 0.5H), 3.36 (s, 3H), 2.98-3.14(m, 1.5H), 2.79-2.97 (m, 1H), 2.60-2.77 (m, 1H), 2.46-2.60 (m, 2H), 1.65(d, J=6.3 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.26 (d, J=7.8 Hz, 1.5H),0.98-1.15 (m, 4H)

LC-MS: m/z 483.2 (M+H)⁺

Compound 311 (General Procedure 8)5-(1-(4-chlorophenyl)ethoxy)-6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.23-7.40 (m, 4H), 6.95 (d, J=3.8 Hz, 1H), 5.13(q, J=6.1 Hz, 1H), 4.85 (br. s., 0.5H), 4.49 (d, J=13.1 Hz, 0.5H), 4.16(br. s., 0.5H), 3.79-3.98 (m, 2H), 3.63-3.78 (m, 2.5H), 3.42-3.57 (m,0.5H), 3.36 (s, 3H), 2.98-3.13 (m, 1.5H), 2.77-2.97 (m, 1H), 2.60-2.76(m, 1H), 2.43-2.60 (m, 2H), 1.65 (d, J=6.3 Hz, 3H), 1.33-1.39 (m, 1.5H),1.22-1.29 (m, 1.5H), 0.97-1.13 (m, 4H)

LC-MS: m/z 483.2 (M+H)⁺

Compound 312 (General Procedure 8)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-nitrobenzyloxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.33 (s, 1H), 8.24 (dd, J=8.2, 1.2 Hz, 1H),7.72-7.84 (m, 1H), 7.54-7.67 (m, 1H), 7.21 (s, 1H), 5.13 (s, 2H), 4.88(br. s., 0.5H), 4.51 (d, J=13.7 Hz, 0.5H), 4.19 (br. s., 0.5H),3.86-4.03 (m, 2H), 3.63-3.84 (m, 2.5H), 3.53 (br. s., 0.5H), 3.37 (s,3H), 3.04-3.18 (m, 1.5H), 2.84-3.04 (m, 1H), 2.62-2.78 (m, 1H),2.42-2.61 (m, 2H), 1.39 (d, J=6.7 Hz, 1.5H), 1.29 (d, J=6.7 Hz, 1.5H),0.97-1.19 (m, 4H)

LC-MS: m/z 480.2 (M+H)⁺

Compound 341 (General Procedure 8)(R)-5-(3-aminobenzyloxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.13-7.24 (m, 2H), 6.79 (d, J=7.8 Hz, 1H), 6.74(s, 1H), 6.67 (dd, J=8.0, 1.5 Hz, 1H), 4.95 (s, 2H), 4.87 (br. s.,0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.81-3.98 (m,2H), 3.73 (t, J=6.1 Hz, 2.5H), 3.53 (d, J=8.8 Hz, 0.5H), 3.37 (s, 3H),3.01-3.16 (m, 1.5H), 2.81-3.00 (m, 1H), 2.61-2.79 (m, 1H), 2.46-2.61 (m,2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 0.95-1.14 (m,4H)

LC-MS: m/z 450.2 (M+H)⁺

Compound 381 (General Procedure 8)(R)—N-(3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)methyl)phenyl)acrylamide

¹H NMR (CHLOROFORM-d) δ 8.11 (br. s., 1H), 7.82 (br. s., 1H), 7.52 (d,J=8.3 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.13-7.23 (m, 2H), 6.45 (dd,J=16.8, 1.3 Hz, 1H), 6.31 (dd, J=16.8, 10.0 Hz, 1H), 5.76 (dd, J=10.2,1.4 Hz, 1H), 4.99 (s, 2H), 4.86 (br. s., 0.5H), 4.50 (d, J=13.6 Hz,0.5H), 4.18 (br. s., 0.5H), 3.81-3.99 (m, 2H), 3.72 (t, J=6.0 Hz, 2.5H),3.45-3.59 (m, 0.5H), 3.35 (s, 3H), 3.00-3.16 (m, 1.5H), 2.81-2.99 (m,1H), 2.62-2.79 (m, 1H), 2.41-2.62 (m, 2H), 1.39 (d, J=6.8 Hz, 1.5H),1.25-1.32 (m, 1.5H), 0.94-1.15 (m, 4H)

LC-MS: m/z 504.2 (M+H)⁺

Compound 382 (General Procedure 8)(R)-2-bromo-N-(3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)methyl)phenyl)acetamide

¹H NMR (CHLOROFORM-d) δ 8.52 (s, 1H), 7.73 (s, 1H), 7.48 (d, J=8.0 Hz,1H), 7.38 (t, J=7.8 Hz, 1H), 7.12-7.26 (m, 2H), 5.02 (s, 2H), 4.87 (br.s., 0.5H), 4.50 (d, J=13.3 Hz, 0.5H), 4.19 (d, J=8.5 Hz, 0.5H), 4.03 (s,2H), 3.81-3.99 (m, 2H), 3.64-3.81 (m, 2.5H), 3.45-3.61 (m, 0.5H), 3.36(s, 3H), 3.02-3.18 (m, 1.5H), 2.82-3.02 (m, 1H), 2.62-2.80 (m, 1H),2.42-2.62 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.22-1.33 (m, 1.5H),0.95-1.14 (m, 4H)

LC-MS: m/z 570.1 (M+H)⁺

Compound 388 (General Procedure 8)6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(1-(pyridin-4-yl)ethoxy)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.57-8.70 (m, 2H), 7.33 (d, J=6.0 Hz, 2H), 6.96(d, J=3.3 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 4.86 (br. s., 0.5H), 4.49 (d,J=12.8 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.81-4.05 (m, 2H), 3.63-3.81 (m,2.5H), 3.51 (d, J=15.3 Hz, 0.5H), 3.36 (s, 3H), 3.07 (t, J=12.9 Hz,1.5H), 2.81-3.00 (m, 1H), 2.60-2.78 (m, 1H), 2.46-2.60 (m, 2H), 1.67 (d,J=6.5 Hz, 3H), 1.36 (d, J=5.0 Hz, 1.5H), 1.24-1.28 (m, 1.5H), 0.99-1.16(m, 4H)

LC-MS: m/z 450.2 (M+H)⁺

Compound 389 (General Procedure 8)N-(4-(1-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)ethyl)phenyl)acrylamide

¹H NMR (CHLOROFORM-d) δ 8.03 (br. s., 1H), 7.56-7.64 (m, 2H), 7.30 (d,J=8.3 Hz, 2H), 6.90-7.05 (m, 1H), 6.43 (dd, J=16.8, 1.3 Hz, 1H), 6.29(dd, J=16.8, 10.0 Hz, 1H), 5.74 (dd, J=10.0, 1.3 Hz, 1H), 5.05-5.19 (m,1H), 4.85 (br. s., 0.5H), 4.48 (d, J=12.5 Hz, 0.5H), 4.16 (br. s.,0.5H), 3.65-3.95 (m, 5.5H), 3.50 (d, J=11.3 Hz, 0.5H), 3.34 (s, 3H),2.97-3.14 (m, 1.5H), 2.77-2.95 (m, 1H), 2.61-2.77 (m, 1H), 2.47-2.61 (m,2H), 1.65 (d, J=6.3 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.26 (d, J=5.0Hz, 1.5H), 0.97-1.15 (m, 4H)

LC-MS: m/z 518.2 (M+H)⁺

Compound 400 (General Procedure 8)(R,E)-N-(3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)methyl)phenyl)but-2-enamide

¹H NMR (CHLOROFORM-d) δ 7.75 (br. s., 1H), 7.47 (d, J=8.0 Hz, 1H),7.30-7.40 (m, 2H), 7.10-7.23 (m, 2H), 6.88-7.09 (m, 1H), 5.96 (dd,J=15.1, 1.5 Hz, 1H), 5.01 (s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J=13.6Hz, 0.5H), 4.18 (br. s., 0.5H), 3.82-4.00 (m, 2H), 3.64-3.80 (m, 2.5H),3.46-3.62 (m, 0.5H), 3.36 (s, 3H), 3.01-3.16 (m, 1.5H), 2.83-3.01 (m,1H), 2.62-2.77 (m, 1H), 2.44-2.61 (m, 2H), 1.93 (dd, J=6.9, 1.6 Hz, 3H),1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=7.0 Hz, 1.5H), 0.95-1.13 (m, 4H)

LC-MS: m/z 518.2 (M+H)⁺

Compound 407 (General Procedure 8)N-(3-(1-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yloxy)ethyl)phenyl)acrylamide

¹H NMR (CHLOROFORM-d) δ 7.75 (br. s., 1H), 7.63 (br. s., 1H), 7.46 (br.s., 1H), 7.34 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.94-7.01 (m,1H), 6.46 (dd, J=16.8, 1.3 Hz, 1H), 6.28 (dd, J=16.9, 10.2 Hz, 1H), 5.79(dd, J=10.3, 1.0 Hz, 1H), 5.13 (q, J=6.1 Hz, 1H), 4.86 (br. s., 0.5H),4.49 (d, J=13.3 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.78-3.95 (m, 2H),3.63-3.78 (m, 2.5H), 3.52 (d, J=14.6 Hz, 0.5H), 3.37 (s, 3H), 2.98-3.14(m, 1.5H), 2.79-2.97 (m, 1H), 2.63-2.78 (m, 1H), 2.48-2.63 (m, 2H), 1.68(d, J=6.3 Hz, 3H), 1.38 (d, J=6.3 Hz, 1.5H), 1.24-1.30 (m, 1.5H),1.00-1.14 (m, 4H)

LC-MS: m/z 518.2 (M+H)⁺

Compound 827 (General Procedure 6)(R)-2-cyclopropyl-6-(3-cyclopropyl-4-hexanoylpiperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.69 (d, J=4.7 Hz, 1H), 7.23 (s, 1H), 7.07 (d,J=4.7 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz, 1H), 6.19-6.36 (m, 1H),5.47-5.63 (m, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H),4.10 (br. s., 0.65H), 3.64-3.91 (m, 1.35H), 2.88-3.38 (m, 2H), 2.37 (br.s., 2H), 2.21 (s, 3H), 1.61-1.73 (m, 2H), 1.51-1.61 (m, 1H), 1.44 (br.s., 1H), 1.35 (br. s., 4H), 1.04-1.17 (m, 2H), 0.90-0.98 (m, 3H), 0.87(dd, J=8.1, 3.1 Hz, 2H), 0.60 (br. s., 1H), 0.55 (br. s., 1H), 0.23-0.50(m, 2H)

LC-MS: m/z 484.3 (M+H)⁺

Compound 826 (General Procedure 6)(R)-6-(4-(3-cyclobutylpropanoyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.70 (d, J=5.0 Hz, 1H), 7.25 (s, 1H), 7.09 (d,J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H),5.51-5.64 (m, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.0 Hz, 1H),4.09 (br. s., 0.6H), 3.63-3.92 (m, 1.4H), 3.01-3.13 (m, 2H), 2.25-2.38(m, 2H), 2.22 (s, 3H), 2.00-2.13 (m, 4H), 1.82-1.90 (m, 2H), 1.75 (q,J=7.4 Hz, 2H), 1.61-1.69 (m, 2H), 1.56 (td, J=8.3, 4.0 Hz, 1H), 1.12(br. s., 2H), 0.80-0.94 (m, 2H), 0.61 (br. s., 1H), 0.55 (br. s., 1H),0.44 (br. s., 2H)

LC-MS: m/z 496.3 (M+H)⁺

Compound 825 (General Procedure 6)(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-cyclopropylpropanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.72 (d, J=5.0 Hz, 1H), 7.26 (s, 1H), 7.09 (d,J=4.7 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.27 (d, J=17.6 Hz, 1H),5.52-5.65 (m, 1H), 4.34 (d, J=12.6 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H),4.02-4.17 (m, 0.6H), 3.71-3.95 (m, 1.4H), 2.95-3.4 (m, 2H), 2.45-2.56(m, 1H), 2.36 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 1.63-1.70 (m, 2H), 1.11(br. s., 2H), 0.75-0.89 (m, 3H), 0.51-0.74 (m, 3H), 0.34-0.50 (m, 4H),0.10 (d, J=4.1 Hz, 2H)

LC-MS: m/z 482.2 (M+H)⁺

Compound 582 (General Procedure 7)(R)-5-((5-cyano-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)amino)picolinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.18-8.17 (d, 1H), 7.61 (s, 1H), 7.51-7.49 (d,1H), 6.89-6.86 (dd, 1H), 6.38 (s, 1H), 4.87 (s, 0.5H), 4.53-4.50 (d,0.5H); 4.27-4.16 (dd, 2H) 3.92 (s, 2H) 3.75-3.10 (m, 4H) 2.69-2.51 (m,2H), 2.07-2.02 (m, 1H), 1.41-1.26 (m, 3H), 1.43-1.10 (m, 2H), 1.04-1.01(m, 2H).

LC-MS: m/z 432.2 (M+H)⁺

Compound 577 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((6-vinylpyridin-3-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.15-8.14 (d, 1H), 7.58 (s, 1H), 7.26-7.23 (d,1H), 6.97-6.94 (dd, 1H), 6.79-6.72 (q, 1H), 6.03-5.98 (dd, 1H), 5.58 (s,1H), 5.36-5.33 (dd, 1H), 4.88 (s, 0.5H), 4.54-4.51 (d, 0.5H); 4.20-4.09(dd, 2H) 3.93 (s, 2H) 3.75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m,2H), 2.18-2.10 (m, 1H), 1.41-1.26 (m, 3H), 1.43-1.30 (m, 2H), 1.13-1.11(m, 2H), 1.03-1.09 (m, 2H).

LC-MS: m/z 433.2 (M+H)⁺

Compound 298 (General Procedure 6)(R)-6-cyclopropyl-5-(4-fluorophenyl)-4-(methoxymethyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ t: 7.21-7.27 (m, 2H), 7.11-7.19 (m, 2H),4.85-4.95 (s, 0.5H), 4.45-4.57 (m, 0.5H), 4.05-4.27 (m, 4H), 3.74 (t,J=6.4 Hz, 2.5H), 3.57-3.63 (m, 0.5H), 3.35-3.40 (m, 3H), 3.29 (s, 3H),3.09-3.26 (m, 2H), 2.59 (br. s., 1H), 1.60-1.70 (m, 1H), 1.38-1.44 (m,1H), 1.30 (d, J=6.8 Hz, 2H), 1.25 (s, 1H), 1.04-1.10 (m, 2H), 0.81-0.88(m, 2H).

LC-MS: m/z 487.2 (M+H)⁺

Compound 823 (General Procedure 6)2-Cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-ethyl-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.57-8.87 (m, 1H), 7.25 (s, 1H), 7.02-7.16 (m,1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.30 (d, J=17.3 Hz, 1H), 5.59 (d,J=10.9 Hz, 1H), 5.27 (t, J=6.6 Hz, 1H), 4.51-4.78 (m, 2H), 4.30-4.42 (m,1H), 4.26 (d, J=11.4 Hz, 1H), 4.09 (d, J=9.1 Hz, 1H), 3.84-3.98 (m, 1H),3.56-3.84 (m, 1H), 2.95-3.45 (m, 3H), 2.68-2.92 (m, 2H), 2.41-2.63 (m,3H), 1.49-1.55 (m, 1H), 1.34 (d, J=8.2 Hz, 1H), 1.10 (t, J=7.6 Hz, 5H),0.80-0.94 (m, 3H), 0.35-0.75 (m, 4H)

LC-MS: m/z 498.3 (M+H)⁺

Compound 805 (General Procedure 6)2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(tetrahydrofuran-2-yl)acetyl)piperazin-1-yl)-4-methyl-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d,J=5.0 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.22-6.40 (m, 1H), 5.57(dd, J=10.9, 0.9 Hz, 1H), 4.60-4.70 (m, 0.5H), 4.18-4.41 (m, 3H),4.02-4.15 (m, 0.5H), 3.89 (d, J=7.3 Hz, 1.5H), 3.63-3.82 (m, 1.5H),2.90-3.45 (m, 3H), 2.64-2.85 (m, 1H), 2.53 (dd, J=14.8, 6.0 Hz, 1H),2.08-2.32 (m, 4H), 1.88-2.00 (m, 2H), 1.51-1.69 (m, 2H), 1.43 (d, J=13.8Hz, 1H), 1.11 (s, 2H), 0.87 (dd, J=7.9, 2.9 Hz, 2H), 0.35-0.66 (m, 4H)

LC-MS: m/z 498.3 (M+H)⁺

Compound 806 (General Procedure 6)2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(5-oxotetrahydrofuran-2-yl)acetyl)piperazin-1-yl)-4-methyl-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.71 (d, J=4.7 Hz, 1H), 7.25 (s, 1H), 7.09 (d,J=4.7 Hz, 1H), 6.90 (dd, J=17.3, 10.9 Hz, 1H), 6.31 (d, J=17.3 Hz, 1H),5.60 (d, J=11.2 Hz, 1H), 4.94-5.08 (m, 1H), 4.17-4.45 (m, 2H), 4.08 (s,1H), 3.79 (s, 2H), 2.80-3.45 (m, 4H), 2.51-2.73 (m, 4H), 2.19-2.28 (m,3H), 1.57 (td, J=8.1, 4.0 Hz, 1H), 1.12 (s, 3H), 0.88 (dd, J=7.9, 3.2Hz, 3H), 0.25-0.74 (m, 4H)

LC-MS: m/z 512.3 (M+H)⁺

Compound 808 (General Procedure 7)2-(5-cyano-2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)pyridin-3-ylamino)pyrimidine-4-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.59 (d, J=4.7 Hz, 1H), 7.87-8.13 (m, 1H),7.00-7.17 (m, 2H), 5.10-5.32 (m, 2H), 4.67-4.83 (m, 1H), 4.47-4.63 (m,1H), 4.39 (d, J=11.7 Hz, 1H), 4.30 (d, J=12.3 Hz, 1H), 4.08 (d, J=7.3Hz, 1H), 3.92 (d, J=12.9 Hz, 1H), 3.64-3.84 (m, 1H), 3.18-3.45 (m, 1H),2.93-3.18 (m, 3H), 2.54 (d, J=6.7 Hz, 1H), 1.94-2.14 (m, 2H), 1.86 (br.s., 2H), 1.46 (d, J=8.2 Hz, 1H), 1.39 (br. s., 1H), 1.33 (br. s., 1H),1.27 (s, 1H), 0.97-1.23 (m, 4H), 0.63 (br. s., 1H), 0.54 (br. s., 1H),0.27-0.50 (m, 2H).

LC-MS: m/z 485.2 (M+H)⁺

Compound 809 (General Procedure 7)5-(4-cyanopyridin-2-ylamino)-6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ: 8.65 (d, J=5.3 Hz, 1H), 7.65 (s, 1H), 7.39 (s,1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H),6.20-6.35 (m, 1H), 5.51-5.65 (m, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.29-4.48(m, 1H), 4.05-4.29 (m, 2H), 4.00 (br. s., 1H), 3.80 (br. s., 1H),3.62-3.77 (m, 1H), 3.54 (br. s., 2H), 3.22 (d, J=12.6 Hz, 2H), 3.09 (t,J=10.9 Hz, 1H), 2.40-2.54 (m, 3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m,11H), 0.94-1.10 (m, 3H), 0.74-0.94 (m, 2H), 0.65 (br. s., 2H), 0.47 (br.s., 3H).

LC-MS: m/z 484.2 (M+H)⁺

Compound 803 (General Procedure 6)2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(3-(oxetan-2-yl)propanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d,J=3.8 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H),5.45-5.62 (m, 1H), 4.88 (s, 1H), 4.64-4.74 (m, 1H), 4.54 (dt, J=8.8, 5.9Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 4.18-4.29 (m, 1H), 4.03-4.15 (m, 1H),3.60-3.90 (m, 1H), 3.09-3.39 (m, 2H), 2.94-3.09 (m, 1H), 2.66-2.78 (m,1H), 2.25-2.60 (m, 3H), 2.21 (s, 3H), 2.01-2.14 (m, 2H), 1.51-1.68 (m,1H), 1.43 (d, J=12.9 Hz, 1H), 1.00-1.16 (m, 2H), 0.87 (dd, J=7.9, 2.9Hz, 2H), 0.25-0.65 (m, 4H)

LC-MS: m/z 498.3 (M+H)⁺

Compound 802 (General Procedure 5)2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(5-oxotetrahydrofuran-2-yl)acetyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.67 (d, J=5.0 Hz, 1H), 7.60-7.71 (m, 1H), 7.40(s, 1H), 7.21-7.27 (m, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.29 (d,J=17.3 Hz, 1H), 5.58 (d, J=10.9 Hz, 1H), 4.94-5.06 (m, 1H), 4.35-4.75(m, 2.5H), 4.01-4.09 (m, 0.5H), 3.70-3.81 (m, 1.5H), 2.90-3.40 (m,3.5H), 2.50-2.79 (m, 4H), 1.98-2.04 (m, 1H), 1.29-1.37 (m, 2H), 1.22(dt, J=7.0, 3.5 Hz, 2H), 0.97-1.06 (m, 2H), 0.26-0.70 (m, 4H)

LC-MS: m/z 498.2 (M+H)⁺

Compound 801 (General Procedure 5)2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(tetrahydrofuran-2-yl)acetyl)piperazin-1-yl)-2′-vinyl-[3,4′-bipyridine]-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.65 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.39 (s,1H), 7.23 (d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.28 (d,J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.50-4.62 (m, 1H), 4.43 (d,J=12.9 Hz, 1H), 4.21-4.35 (m, 1H), 4.05-4.11 (m, 1H), 3.80-3.92 (m,1.5H), 3.62-3.80 (m, 1.5H), 3.07-3.41 (m, 3H), 2.45-2.97 (m, 2H),2.15-2.20 (m, 1H), 1.98-2.05 (m, 2H), 1.92 (dt, J=14.2, 6.9 Hz, 2H),1.62 (d, J=7.3 Hz, 1H), 1.16-1.24 (m, 2H), 1.00 (dd, J=7.5, 3.4 Hz, 2H),0.34-0.71 (m, 4H)

LC-MS: m/z 484.3 (M+H)⁺

Compound 824 (General Procedure 7)6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-5-((2-(hydroxymethyl)pyridin-4-yl)amino)nicotinonitrile

¹H NMR (400 MHz, MeOD) δ 8.08 (d, J=6.5 Hz, 1H), 7.80 (d, J=2.2 Hz, 1H),6.81 (d, J=2.0 Hz, 1H), 6.71 (dd, J=6.4, 2.3 Hz, 1H), 6.18-6.11 (m, 1H),5.62 (dd, J=6.8, 5.5 Hz, 1H), 5.24 (s, 1H), 4.66 (d, J=7.0 Hz, 3H), 4.51(d, J=13.1 Hz, 1H), 4.37 (s, 1H), 4.14-3.97 (m, 1H), 3.71 (dd, J=10.8,4.4 Hz, 2H), 3.62 (s, 1H), 3.18-3.04 (m, 1H), 2.84 (s, 1H), 2.49 (d,J=6.5 Hz, 1H), 2.17-2.09 (m, 1H), 1.96 (s, 1H), 1.53-1.25 (m, 3H),1.21-1.13 (m, 2H), 1.04 (dd, J=7.7, 3.4 Hz, 2H), 0.71-0.36 (m, 4H).

LC-MS: m/z 489.2 (M+H)⁺

Compound 810 (General Procedure 5) Sodium(R)-3-(4-(5-cyano-2-cyclopropyl-2′-vinyl-[3,4′-bipyridin]-6-yl)-2-cyclopropylpiperazin-1-yl)-3-oxopropylphosphate

¹H NMR (400 MHz, D₂O) δ 8.37 (d, J=5.0 Hz, 1H), 7.61 (s, 1H), 7.40 (s,1H), 7.26 (s, 1H), 6.74 (dd, J=17.5, 11.3 Hz, 1H), 6.04 (d, J=17.8 Hz,1H), 5.51 (d, J=11.2 Hz, 1H), 4.47 (s, 1H), 4.35 (s, 2H), 3.91 (d, J=6.7Hz, 3H), 3.82 (s, 1H), 3.56 (q, J=7.1 Hz, 2H), 3.20 (s, 1H), 2.78 (s,1H), 2.71-2.63 (m, 1H), 1.92 (s, 1H), 1.55 (s, 4H), 1.18 (s, 2H), 0.89(s, 1H), 0.45-0.46 (m, 2H), 0.37-0.22 (m, 2H).

LC-MS: m/z 568.2 (M+H)⁺

Compound 828 (General Procedure 7)

1H NMR (CHLOROFORM-d) δ 8.07 (d, J=5.3 Hz, 1H), 7.81 (s, 1H), 7.02 (br.s., 1H), 6.71-6.84 (m, 1H), 6.55 (dd, J=17.6, 10.9 Hz, 1H), 6.38 (s,1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.18-4.44 (m,3H), 4.11 (q, J=7.0 Hz, 1H), 3.81-3.99 (m, 2H), 3.62-3.81 (m, 2H), 3.11(d, J=12.9 Hz, 2H), 3.04 (m, 1H), 2.73 (d, J=6.5 Hz, 1H), 2.08-2.28 (m,2H), 1.82-1.97 (m, 2H), 1.59 (dd, J=12.0, 7.9 Hz, 1H), 1.25 (t, J=7.0Hz, 1H), 1.04-1.18 (m, 2H), 0.88-1.02 (m, 2H), 0.51-0.59 (m, 2H),0.42-0.49 (m, 2H)

LC-MS: m/z 499.2 (M+H)⁺

Compound 829 (General Procedure 7)

1H NMR (CHLOROFORM-d) δ 7.56 (s, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.11 (br,s, 1H), 5.79 (dd, J=7.3, 2.3 Hz, 1H), 5.58 (br. s., 1H), 5.26 (t, J=6.6Hz, 1H), 4.71 (td, J=7.9, 6.2 Hz, 1H), 4.56 (m, 1H), 4.43 (d, J=12.3 Hz,1H), 4.32 (d, J=12.6 Hz, 1H), 4.06 (d, J=9.1 Hz, 0.5H), 3.92 (d, J=12.3Hz, 0.5H), 3.69-3.82 (m, 1H), 3.47 (s, 3H), 3.08-3.34 (m, 2H), 2.92-3.08(m, 2.5H), 2.78-2.90 (m, 1.5H), 2.54 (d, J=7.3 Hz, 1H), 2.06-2.17 (m,1H), 1.27 (s, 1H), 1.06-1.16 (m, 2H), 0.98-1.05 (m, 2H), 0.53-0.63 (m,2H), 0.30-0.49 (m, 2H)

LC-MS: m/z 489.2 (M+H)⁺

Compound 830 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-hexanoylpiperazin-1-yl)-5-(4-vinylpyridin-2-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.02 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 6.82 (d,J=5.3 Hz, 1H), 6.56 (dd, J=17.3, 10.9 Hz, 1H), 6.34 (s, 1H), 5.90 (d,J=17.6 Hz, 1H), 5.49 (d, J=10.9 Hz, 1H), 4.40 (d, J=12.9 Hz, 1H), 4.29(d, J=12.0 Hz, 1H), 4.11 (br. s., 1H), 3.80 (br. s., 2H), 3.16 (br. s.,2H), 2.90-3.11 (m, 1H), 2.25-2.45 (m, 5H), 1.56-1.73 (m, 4H), 1.20-1.48(m, 4H), 1.07-1.20 (m, 2H), 0.82-1.07 (m, 2H).

LC-MS: m/z 485.2 (M+H)⁺

Compound 818 (General Procedure 5)

¹H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.7 Hz, 1H), 7.66 (s, 1H), 7.41 (s,1H), 7.22-7.28 (m, 1H), 6.90 (dd, J=17.3, 10.9 Hz, 1H), 6.31 (d, J=17.3Hz, 1H), 5.60 (d, J=10.9 Hz, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.43 (dd,J=12.9, 2.1 Hz, 1H), 4.14 (m, 2H), 3.72 (m, 1H), 3.43-3.63 (m, 2H), 3.22(d, J=11.4 Hz, 2H), 3.01-3.16 (m, 2H), 2.06-2.11 (m, 1H), 1.79-2.09 (m,1H), 1.65 (br. s., 1H), 1.40-1.53 (m, 1H), 1.17-1.25 (m, 2H), 0.96-1.08(m, 2H), 0.66-0.75 (m, 2H), 0.39-0.61 (m, 2H)

LC-MS: m/z 483.7 (M+H)⁺

Compound 821 (General Procedure 5)

1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.3 Hz, 1H), 7.65 (s, 1H), 7.33-7.46(m, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.5, 10.7 Hz, 1H),6.24-6.39 (m, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H), 5.01 (t, J=6.3 Hz,1H), 4.56 (m, 1.5H), 4.44 (d, J=14.1 Hz, 1H), 3.79 (m, 1H), 3.22 (m,1.5H), 2.70 (d, J=6.7 Hz, 1H), 2.49-2.65 (m, 3H), 1.90-2.14 (m, 4H),1.35 (m, 1H), 1.21 (m, 3H), 0.92-1.08 (m, 2H), 0.48 (m, 4H)

LC-MS: m/z 498.7 (M+H)⁺

Compound 822 (General Procedure 5)

¹H NMR (CHLOROFORM-d) δ 8.64 (d, J=4.7 Hz, 1H), 7.53 (s, 1H), 7.38 (s,1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz, 1H),6.18-6.36 (m, 1H), 5.49-5.62 (m, 1H), 4.67-4.71 (m, 0.5H), 4.54 (d,J=12.6 Hz, 1H), 4.36-4.46 (m, 1H), 4.28 (quin, J=6.5 Hz, 1H), 4.11 (d,J=7.9 Hz, 0.5H), 3.81-4.00 (m, 1.5H), 3.63-3.79 (m, 1.5H), 3.08-3.20 (m,1H), 2.64-2.85 (m, 2H), 2.46-2.60 (m, 1H), 2.08-2.24 (m, 1H), 1.97-2.08(m, 1H), 1.82-1.97 (m, 2H), 1.52-1.70 (m, 1H), 1.26-1.30 (m, 2H),1.12-1.24 (m, 2H), 0.92-1.05 (m, 2H), 0.49-0.73 (m, 2H), 0.45 (m, 2H)

LC-MS: m/z 484.7 (M+H)⁺

Compound 811 (General Procedure 6)

¹H NMR (CHLOROFORM-d) δ 7.23 (s, 1H), 7.07 (dd, J=5.0, 1.2 Hz, 1H), 6.87(dd, J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (dd, J=10.9,1.2 Hz, 1H), 4.32 (d, J=12.9 Hz, 1H), 4.23 (dd, J=12.6, 2.1 Hz, 1H),4.14 (m, 1H), 3.99 (br. s., 1H), 3.72 (br. s., 1.5H), 3.42-3.57 (m,2.5H), 3.10-3.25 (m, 2H), 2.98-3.10 (m, 3H), 2.10-2.38 (m, 4H),1.51-1.62 (m, 1H), 1.45 (dq, J=14.7, 7.3 Hz, 1H), 1.07-1.17 (m, 2H),0.88 (dd, J=7.9, 3.2 Hz, 2H), 0.66 (br. s., 1H), 0.30-0.59 (m, 3H)

LC-MS: m/z 497.7 (M+H)⁺

Compound 814 (General Procedure 5)(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-(2-oxopyrrolidin-1-yl)acetyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.65 (d, J=5.3 Hz, 1H), 7.65 (s, 1H), 7.39 (s,1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H),6.20-6.35 (m, 1H), 5.51-5.65 (m, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.29-4.48(m, 1H), 4.05-4.29 (m, 2H), 4.00 (br. s., 1H), 3.80 (br. s., 1H),3.62-3.77 (m, 1H), 3.54 (br. s., 2H), 3.22 (d, J=12.6 Hz, 2H), 3.09 (t,J=10.9 Hz, 1H), 2.40-2.54 (m, 3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m, 4H),0.94-1.10 (m, 3H), 0.74-0.94 (m, 2H), 0.65 (br. s., 2H), 0.47 (br. s.,3H).

LC-MS: m/z 497.2 (M+H)⁺

Compound 815 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(4-hydroxybutanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 6.86(dd, J=5.5, 1.1 Hz, 1H), 6.80 (s, 1H), 6.59 (dd, J=17.6, 10.9 Hz, 1H),6.44 (s, 1H), 5.93 (d, J=17.5 Hz, 1H), 5.51 (d, J=10.9 Hz, 1H),4.75-4.61 (m, 0.5H), 4.37 (d, J=12.8 Hz, 1H), 4.27 (d, J=12.6 Hz, 1H),4.10 (d, J=7.2 Hz, 0.5H), 3.85 (d, J=10.0 Hz, 0.5H), 3.81-3.65 (m,2.5H), 3.30 (dd, J=9.3, 5.7 Hz, 1H), 3.22-3.12 (m, 1H), 3.12-2.97 (m,1H), 2.66-2.43 (m, 2H), 2.21-2.14 (m, 1H), 1.97 (dd, J=12.0, 6.2 Hz,2H), 1.46 (dd, J=8.5, 6.8 Hz, 1H), 1.14 (dd, J=7.1, 4.0 Hz, 2H), 1.04(ddd, J=9.5, 6.4, 3.0 Hz, 2H), 0.77-0.38 (m, 4H).

LC-MS: m/z 473.2 (M+H)⁺

Compound 816 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-(2-oxopyrrolidin-1-yl)acetyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=5.6 Hz, 1H), 7.83 (s, 1H), 7.19 (s,1H), 6.87 (dd, J=5.7, 1.3 Hz, 1H), 6.60 (dd, J=17.5, 10.9 Hz, 1H), 6.44(s, 1H), 5.95 (d, J=17.5 Hz, 1H), 5.54 (d, J=10.9 Hz, 1H), 4.55 (s,0.5H), 4.39 (d, J=12.9 Hz, 1H), 4.28 (dd, J=12.7, 2.1 Hz, 1H), 4.19 (s,1H), 4.00 (s, 0.5H), 3.75 (dd, J=30.5, 3.9 Hz, 2H), 3.55 (s, 2H), 3.33(s, 1H), 3.18 (d, J=11.9 Hz, 1H), 3.05 (t, J=13.2 Hz, 1H), 2.47 (t,J=8.0 Hz, 2H), 2.21-2.16 (m, 1H), 2.12 (dt, J=15.4, 7.6 Hz, 2H), 1.28(d, J=5.1 Hz, 1H), 1.19-1.10 (m, 2H), 1.05 (ddd, J=9.0, 6.6, 2.5 Hz,2H), 0.78-0.41 (m, 4H).

LC-MS: m/z 513.6 (M+H)⁺

Compound 817 (General Procedure 7)(R)-2-(4-(2-cyclobutylacetyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=5.6 Hz, 1H), 7.80 (s, 1H), 6.87(dd, J=5.7, 1.2 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.43 (s, 1H),5.95 (d, J=17.5 Hz, 1H), 5.54 (d, J=10.8 Hz, 1H), 4.65 (d, J=11.7 Hz,0.4H), 4.41 (d, J=12.6 Hz, 1H), 4.30 (d, J=12.3 Hz, 1H), 4.09 (d, J=5.2Hz, 0.6H), 3.91-3.59 (m, 1.5H), 3.34-3.10 (m, 1.5H), 3.09-2.94 (m, 1H),2.74 (dt, J=15.5, 7.8 Hz, 1H), 2.52 (s, 2H), 2.25-2.12 (m, 3H),1.98-1.82 (m, 2H), 1.82-1.63 (m, 2H), 1.28 (s, 1H), 1.19-1.09 (m, 2H),1.04 (dt, J=6.9, 3.0 Hz, 2H), 0.78-0.34 (m, 4H).

LC-MS: m/z 483.6 (M+H)⁺

Compound 812 (General Procedure 7)6-cyclopropyl-2-((3R)-3-cyclopropyl-4-(3-(oxetan-2-yl)propanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=5.4 Hz, 1H), 7.85 (s, 1H), 6.83(dd, J=5.4, 1.3 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.41 (s, 1H),6.39 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.47 (d, J=11.0 Hz, 1H), 4.89 (s,1H), 4.70 (dd, J=14.1, 7.8 Hz, 1H), 4.55 (dd, J=14.7, 5.8 Hz, 1H), 4.36(d, J=12.8 Hz, 1H), 4.25 (dd, J=12.5, 1.8 Hz, 1H), 4.09 (dd, J=7.2, 2.6Hz, 1H), 3.78 (ddd, J=23.5, 14.1, 6.1 Hz, 1.5H), 3.28 (s, 0.5H), 3.13(d, J=12.4 Hz, 1H), 3.02 (dd, J=21.5, 9.8 Hz, 1H), 2.74 (ddd, J=14.2,11.1, 8.0 Hz, 1H), 2.62-2.47 (m, 1H), 2.46-2.32 (m, 2H), 2.23-1.98 (m,3H), 1.28 (d, J=4.8 Hz, 1H), 1.19-1.09 (m, 2H), 1.02 (ddd, J=9.4, 6.4,3.0 Hz, 2H), 0.75-0.35 (m, 4H).

LC-MS: m/z 499.6 (M+H)⁺

Compound 813 (General Procedure 7)6-cyclopropyl-2-((3R)-3-cyclopropyl-4-(2-(tetrahydrofuran-2-yl)acetyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=5.4 Hz, 1H), 7.84 (s, 1H), 6.84(dd, J=5.4, 1.2 Hz, 1H), 6.59 (dd, J=17.5, 10.8 Hz, 1H), 6.46 (s, 1H),6.41 (s, 1H), 5.91 (d, J=17.6 Hz, 1H), 5.47 (d, J=10.9 Hz, 1H), 4.69 (d,J=13.9 Hz, 0.5H), 4.46-4.33 (m, 1H), 4.28 (dd, J=15.4, 9.1 Hz, 2H), 4.11(d, J=5.3 Hz, 0.5H), 3.98-3.83 (m, 1.5H), 3.75 (dt, J=22.2, 11.1 Hz,1.5H), 3.40-3.09 (m, 2H), 3.09-2.93 (m, 1H), 2.83-2.47 (m, 2H),2.47-2.29 (m, 0.5H), 2.26-2.12 (m, 2H), 2.11-1.99 (m, 0.5H), 1.93 (dt,J=13.7, 7.0 Hz, 2H), 1.28 (d, J=5.3 Hz, 1H), 1.19-1.09 (m, 2H), 1.02(ddd, J=9.8, 6.6, 2.9 Hz, 2H), 0.77-0.32 (m, 4H).

LC-MS: m/z 499.3 (M+H)^(+COMPOUND) 807 (General Procedure 7)

(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methyl-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=6.1 Hz, 1H), 6.69 (dd, J=17.4, 10.9Hz, 1H), 6.57 (s, 1H), 6.45 (s, 1H), 6.21 (d, J=17.6 Hz, 1H), 6.18-6.10(m, 1H), 5.60 (d, J=11.1 Hz, 1H), 4.71 (d, J=13.2 Hz, 0.5H), 4.50-4.37(m, 1.5H), 4.33-4.25 (m, 1H), 3.87 (d, J=13.1 Hz, 0.5H), 3.82-3.67 (m,2H), 3.60 (d, J=10.2 Hz, 0.5H), 3.47 (dd, J=18.2, 7.7 Hz, 0.5H), 3.38(d, J=4.2 Hz, 3H), 3.14 (ddd, J=13.3, 9.5, 5.2 Hz, 1.5H), 3.09-2.94 (m,1H), 2.81-2.56 (m, 2H), 2.38 (s, 3H), 2.25 (dd, J=13.6, 6.4 Hz, 0.5H),2.07 (ddd, J=15.8, 11.1, 6.8 Hz, 1.5H), 1.15-1.09 (m, 1H), 1.04 (dd,J=6.5, 2.9 Hz, 4H), 0.97 (dd, J=7.5, 5.0 Hz, 2H), 0.93 (d, J=6.8 Hz,1.5H), 0.86 (d, J=6.8 Hz, 1.5H).

LC-MS: m/z 489.6 (M+H)⁺

Compound 799 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-methyl-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=5.7 Hz, 1H), 6.70 (dd, J=17.4, 10.8Hz, 1H), 6.50 (s, 1H), 6.33 (s, 1H), 6.16 (d, J=17.4 Hz, 1H), 5.74 (s,1H), 5.48 (dd, J=10.8, 0.9 Hz, 1H), 4.69 (d, J=9.7 Hz, 0.5H), 4.41 (ddd,J=6.7, 6.1, 4.4 Hz, 1.5H), 4.27 (t, J=10.2 Hz, 1H), 4.00-3.86 (m, 2H),3.76 (d, J=13.5 Hz, 0.5H), 3.60-3.52 (m, 1H), 3.50-3.44 (m, 1H),3.17-3.05 (m, 2H), 3.01 (dd, J=11.6, 9.4 Hz, 0.5H), 2.61 (pd, J=11.7,5.1 Hz, 2H), 2.38 (s, 3H), 2.33-2.22 (m, 0.5H), 2.11 (ddd, J=12.7, 9.3,5.2 Hz, 1.5H), 1.11 (ddd, J=8.9, 6.6, 4.7 Hz, 1H), 1.05 (d, J=6.5 Hz,4H), 0.97 (dt, J=7.8, 6.6 Hz, 2H), 0.93 (d, J=6.9 Hz, 1.5H), 0.86 (d,J=6.8 Hz, 1.5H).

LC-MS: m/z 475.2 (M+H)⁺

Compound 798 (General Procedure 7)(R,E)-6-cyclopropyl-2-(3-cyclopropyl-4-(5-hydroxypent-2-enoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=5.3 Hz, 1H), 7.83 (s, 1H),6.89-6.77 (m, 2H), 6.57 (dd, J=17.6, 10.8 Hz, 1H), 6.53-6.43 (m, 1H),6.40 (s, 1H), 6.39-6.26 (m, 1H), 5.88 (d, J=17.5 Hz, 1H), 5.44 (d,J=10.9 Hz, 1H), 4.74-4.43 (m, 0.3H), 4.35 (t, J=11.7 Hz, 1H), 4.26 (d,J=12.5 Hz, 1H), 4.11-3.87 (m, 0.8H), 3.78 (dd, J=11.6, 5.5 Hz, 2H),3.75-3.68 (m, 1H), 3.53 (m, 0.5H), 3.45 (m, 0.5H), 3.42-3.28 (m, 0.5H),3.24-3.11 (m, 1.5H), 3.03 (td, J=12.6, 3.3 Hz, 1H), 2.49 (dd, J=12.5,6.2 Hz, 2H), 2.22-2.15 (m, 1H), 1.45 (d, J=6.5 Hz, 1H), 1.17-1.08 (m,2H), 1.00 (ddd, J=9.4, 6.5, 3.0 Hz, 2H), 0.73-0.32 (m, 4H).

LC-MS: m/z 485.6 (M+H)⁺

Compound 581 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=5.7 Hz, 1H), 7.62 (s, 1H), 6.71(dd, J=17.4, 10.8 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 6.45 (dd, J=5.7, 2.2Hz, 1H), 6.19 (d, J=17.2 Hz, 1H), 5.90 (s, 1H), 5.48 (d, J=11.2 Hz, 1H),4.90 (s, 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.23 (dd, J=31.3, 14.0 Hz,2.5H), 3.94 (s, 2H), 3.74 (d, J=13.6 Hz, 0.5H), 3.57 (t, J=11.0 Hz,0.5H), 3.29 (dd, J=10.5, 6.5 Hz, 1H), 3.15 (dd, J=23.7, 11.6 Hz, 1H),3.09-2.99 (m, 0.5H), 2.62 (m, J=34.8, 15.8 Hz, 2H), 2.12 (td, J=8.1, 4.1Hz, 1H), 1.43 (d, J=6.4 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.13 (dd,J=7.2, 4.2 Hz, 2H), 1.03 (ddd, J=10.0, 6.4, 3.3 Hz, 2H).

LC-MS: m/z 447.6 (M+H)⁺

Compound 642 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=5.9 Hz, 1H), 7.61 (s, 1H), 6.72(dd, J=17.5, 10.9 Hz, 1H), 6.62 (s, 1H), 6.53 (d, J=4.4 Hz, 1H), 6.24(d, J=17.4 Hz, 1H), 5.53 (d, J=10.9 Hz, 1H), 4.92 (s, 1H), 4.55 (d,J=16.6 Hz, 1H), 4.25 (t, J=11.9 Hz, 2H), 4.17 (d, J=13.8 Hz, 1H), 3.82(d, J=8.4 Hz, 1H), 3.76 (t, J=6.2 Hz, 2H), 3.58 (d, J=12.3 Hz, 1H), 3.39(s, 3H), 3.30 (d, J=13.0 Hz, 1H), 3.15 (t, J=11.7 Hz, 1H), 3.06 (d,J=12.2 Hz, 1H), 2.73 (ddd, J=22.9, 14.3, 6.7 Hz, 1H), 2.64-2.53 (m, 1H),2.09 (td, J=7.9, 4.1 Hz, 1H), 1.40 (d, J=5.7 Hz, 2H), 1.30 (d, J=7.1 Hz,2H), 1.13 (dd, J=6.8, 4.1 Hz, 2H), 1.02 (dd, J=7.6, 3.3 Hz, 2H).

LC-MS: m/z 447.2 (M+H)⁺

Compound 643 (General Procedure 7)(R)-5-((2-chloropyridin-4-yl)-amino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=4.9 Hz, 1H), 7.59 (s, 1H), 6.53 (s,1H), 6.50 (s, 1H), 6.00 (s, 1H), 4.91 (s, 1H), 4.55 (d, J=10.6 Hz, 1H),4.29 (d, J=11.2 Hz, 2H), 4.20 (d, J=12.9 Hz, 1H), 3.82 (d, J=13.8 Hz,1H), 3.73 (dt, J=9.5, 5.8 Hz, 2H), 3.57 (t, J=11.0 Hz, 1H), 3.39 (s,3H), 3.30 (d, J=12.0 Hz, 1H), 3.15 (t, J=11.8 Hz, 1H), 3.07 (d, J=12.0Hz, 1H), 2.83-2.65 (m, 1H), 2.60 (dd, J=13.4, 7.5 Hz, 1H), 2.07 (ddd,J=12.6, 7.0, 4.8 Hz, 1H), 1.40 (d, J=6.4 Hz, 2H), 1.34-1.27 (m, 1H),1.13 (s, 2H), 1.09-0.99 (m, 2H).

LC-MS: m/z 455.3 (M+H)⁺

Compound 796 (General Procedure 6)(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-(furan-2-yl)propanoyl)piperazin-1-yl)-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.0 Hz, 1H), 7.31-7.38 (m, 1H), 7.23(s, 1H), 7.07 (d, J=4.1 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H),6.21-6.40 (m, 2H), 6.06 (d, J=2.9 Hz, 1H), 5.57 (d, J=11.4 Hz, 1H), 4.22(d, J=12.6 Hz, 2H), 2.93-3.18 (m, 4H), 2.72 (br. s., 2H), 2.21 (s, 3H),1.33-1.62 (m, 2H), 1.03-1.33 (m, 3H), 0.87 (dd, J=7.9, 3.2 Hz, 2H), 0.44(br. s., 4H).

LC-MS: m/z 508.6 (M+H)⁺

Compound 797 (General Procedure 6)(R)-6-(4-(3-cyclopentylpropanoyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-methyl-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.69 (d, J=4.7 Hz, 1H), 7.23 (s, 1H), 7.07 (d,J=4.4 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.12-6.41 (m, 1H),5.41-5.69 (m, 1H), 4.19-4.48 (m, 2H), 3.96-4.19 (m, 1H), 3.80 (br. s.,1H), 3.15 (br. s., 2H), 3.04 (br. s., 1H), 2.28-2.49 (m, 2H), 2.21 (s,3H), 1.86 (br. s., 1H), 1.80 (br. s., 3H), 1.47-1.72 (m, 8H), 1.11 (br.s., 4H), 0.73-1.00 (m, 3H), 0.60 (br. s., 1H), 0.55 (br. s., 1H),0.23-0.50 (m, 2H).

LC-MS: m/z 510.7 (M+H)⁺

Compound 804 (General Procedure 5) (R)-di-tert-butyl4-(4-(5-cyano-2-cyclopropyl-2′-vinyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazin-1-yl)-4-oxobutylphosphate

¹H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.40 (s,1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.30(d, J=16.7 Hz, 1H), 5.58 (d, J=11.2 Hz, 1H), 4.56 (d, J=12.9 Hz, 1H),4.35-4.49 (m, 1H), 3.99-4.20 (m, 3H), 3.71-3.84 (m, 1H), 2.99-3.22 (m,2H), 2.53 (d, J=5.9 Hz, 1H), 2.00-2.07 (m, 3H), 1.66 (d, J=12.3 Hz, 3H),1.52 (s, 18H), 1.18-1.25 (m, 2H), 0.98-1.06 (m, 2H), 0.62 (br. s., 1H),0.56 (br. s., 1H), 0.47 (d, J=5.0 Hz, 2H)

LC-MS: m/z 650.3 (M+H)⁺

Compound 560 (General Procedure 7)(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-5-(quinolin-4-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.55 (d, J=5.5 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H),8.03 (d, J=8.3 Hz, 1H), 7.80 (t, J=7.3 Hz, 1H), 7.71 (s, 1H), 7.63 (t,J=7.7 Hz, 1H), 6.36 (d, J=5.5 Hz, 1H), 4.52 (d, J=13.3 Hz, 1H), 4.41 (d,J=13.8 Hz, 1H), 4.15 (br. s., 1H), 3.69-3.86 (m, 2H), 3.12-3.35 (m, 4H),2.01-2.13 (m, 1H), 1.33-1.35 (m, 1H), 1.12-1.21 (m, 2H), 0.95-1.07 (m,2H), 0.45-0.73 (m, 4H)

LC-MS: m/z 521.2 (M+H)⁺

Compound 617 (General Procedure 7)(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-vinylpyrimidin-4-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.58-8.68 (m, 1H), 7.72-7.80 (m, 1H), 6.90-7.01(m, 1H), 6.53-6.66 (m, 1H), 6.35-6.48 (m, 1H), 6.27 (s, 1H), 5.62 (dd,J=10.5, 1.3 Hz, 1H), 4.90 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H),4.11-4.34 (m, 2.5H), 3.93 (br. s., 2H), 3.74 (d, J=13.6 Hz, 0.5H),3.50-3.65 (m, 0.5H), 3.45 (br. s., 0.5H), 3.23-3.32 (m, 1H), 3.10-3.20(m, 0.5H), 2.98-3.09 (m, 0.5H), 2.48-2.76 (m, 2H), 2.08-2.16 (m, 1H),1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.10-1.20 (m, 2H),0.97-1.09 (m, 2H)

LC-MS: m/z 434.3 (M+H)⁺

Compound 700 (General Procedure 5)(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile

¹H NMR (CHLOROFORM-d) δ 7.97 (s, 1H), 6.89 (s, 1H), 6.66 (dd, J=17.3,10.5 Hz, 1H), 6.52 (d, J=17.8 Hz, 1H), 5.74 (d, J=10.5 Hz, 1H), 5.41(br. s., 2H), 4.66 (d, J=12.5 Hz, 1H), 4.52 (d, J=12.5 Hz, 1H),3.16-4.28 (m, 5H), 2.33-2.49 (m, 1H), 1.72 (br. s., 2H), 1.21-1.26 (m,2H), 0.98-1.15 (m, 4H), 0.82 (dd, J=7.8, 2.3 Hz, 2H), 0.63 (br. s., 1H),0.36-0.58 (m, 3H)

LC-MS: m/z 456.4 (M+H)⁺

Compound 751 (General Procedure 7)6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-5-(2-vinylpyridin-4-ylamino)nicotinonitrile

¹H NMR (CHLOROFORM-d) δ 8.24 (d, J=5.9 Hz, 1H), 7.62 (s, 1H), 6.70 (dd,J=17.3, 10.9 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H), 6.49 (d, J=5.9 Hz, 1H),6.19 (d, J=17.6 Hz, 1H), 6.04 (br. s., 1H), 5.53 (d, J=10.9 Hz, 1H),5.27 (quin, J=6.7 Hz, 1H), 4.69-4.79 (m, 1H), 4.42-4.58 (m, 2H), 4.35(d, J=12.9 Hz, 1H), 4.09 (d, J=8.8 Hz, 1H), 3.95 (d, J=13.8 Hz, 1H),3.67-3.82 (m, 1H), 2.75-3.34 (m, 5H), 2.55 (d, J=9.1 Hz, 1H), 2.08 (td,J=8.1, 4.0 Hz, 1H), 1.33 (br. s., 1H), 1.10-1.18 (m, 2H), 1.03 (dd,J=7.8, 3.4 Hz, 2H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.47 (d, J=5.9Hz, 2H)

LC-MS: m/z 485.6 (M+H)⁺

Compound 752 (General Procedure 5)2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.35-7.46(m, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.88 (dd, J=17.5, 10.7 Hz, 1H),6.21-6.36 (m, 1H), 5.49-5.61 (m, 1H), 5.27 (quin, J=6.6 Hz, 1H), 4.72(td, J=7.9, 6.2 Hz, 1H), 4.50-4.65 (m, 2H), 4.44 (d, J=12.9 Hz, 1H),4.09 (d, J=8.2 Hz, 0.6H), 3.84-4.02 (m, 0.7H), 3.74 (t, J=12.0 Hz,0.7H), 3.25 (br. s., 1H), 2.91-3.23 (m, 3.5H), 2.55-2.9 (m, 2.5H), 2.55(d, J=8.8 Hz, 1H), 1.97-2.11 (m, 1H), 1.33 (br. s., 1H), 1.18-1.26 (m,2H), 0.94-1.07 (m, 2H), 0.63 (br. s., 1H), 0.56 (br. s., 1H), 0.47 (br.s., 2H)

LC-MS: m/z 470.2 (M+H)⁺

Compound 800 (General Procedure 5)2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(3-(tetrahydrofuran-2-yl)propanoyl)piperazin-1-yl)-2′-vinyl-3,4′-bipyridine-5-carbonitrile

¹H NMR (CHLOROFORM-d) δ: 8.63 (d, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.37 (s,1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.86 (dd, J=17.5, 10.7 Hz, 1H), 6.26(d, J=17.6 Hz, 1H), 5.54 (d, J=10.9 Hz, 1H), 4.53 (d, J=12.9 Hz, 1H),4.41 (d, J=12.6 Hz, 1H), 4.00-4.22 (m, 1H), 3.85 (d, J=6.5 Hz, 3H),3.62-3.77 (m, 2H), 3.08-3.29 (m, 3H), 2.31-2.60 (m, 2H), 1.83-2.11 (m,5H), 1.68-1.83 (m, 1H), 1.46-1.58 (m, 1H), 1.20 (dt, J=7.3, 3.6 Hz, 2H),0.93-1.07 (m, 2H), 0.49-0.76 (m, 2H), 0.43 (br. s., 2H)

LC-MS: m/z 498.7 (M+H)⁺

Having thus described several aspects of several embodiments, it is tobe appreciated various alterations, modifications, and improvements willreadily occur to those skilled in the art. Such alterations,modifications, and improvements are intended to be part of thisdisclosure, and are intended to be within the spirit and scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only.

1. A compound of Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Y is —N(R⁵)—,—N(R₅)—CH₂—, —CH₂—N(R⁵)— or —CH(R⁵)—; each R^(1a) and R^(1b) isindependently hydrogen, —C₁-C₄ alkyl, —N(R⁷)(C₁-C₄ alkylene)-N(R⁷)(C₁-C₄alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R⁷)-aryl,—N(R⁷)C(O)-aryl, —(C₁-C₄ alkylene)-aryl, —(C₁-C₄ alkylene)-heteroaryl,—O—(C₀-C₄ alkylene)-aryl, —O—(C₀-C₄ alkylene)-heteroaryl, —O—(C₀-C₄alkylene)-heterocyclyl, —O—(C₀-C₄ alkylene)-carbocyclyl, —N(R⁷)-aryl, or—N(R⁷)-heteroaryl, —N(R⁹)-aryl, —N(R⁹)-heteroaryl, —O—(C₁-C₄alkeylene)-N(R⁷)C(O)O—(C₁-C₄ alkylene)-aryl, —N(R⁹)—C(O)—(C₂-C₄ alkenyl)wherein: at least one of R^(1a) and R^(1b) is not hydrogen or methyl;any alkylene moiety present in R^(1a) or R^(1b) is optionallysubstituted with OH or F; each R⁷ is independently selected fromhydrogen and C₁-C₄ alkyl; and any aryl, heteroaryl, or heterocyclyl ofR^(1a) or R^(1b) is optionally substituted with one or more substituentsselected from -G-L-M, halo, —NO₂, C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃;G is a bond or a bivalent C₁-C₆ saturated or unsaturated, straight orbranched hydrocarbon chain wherein optionally one, two or threemethylene units of the hydrocarbon chain are independently replaced by—NR⁸—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—,—C(═NR⁸)—, —N═N—, or —C(═N₂)—; L is a covalent bond or a bivalent C₁₋₈saturated or unsaturated, straight or branched, hydrocarbon chain,wherein one, two, or three methylene units of L are optionally andindependently replaced by cyclopropylene, —N(R⁸)C(O)—, —C(O)N(R⁸)—,—N(R⁸)SO₂—, SO₂N(R⁸)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—,—C(═S)—, —C(═NR⁸)—, —N═N—, or —C(═N₂)—; M is E, or a 3-10 memberedmonocyclic or bicyclic, saturated, partially unsaturated, or aromaticring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and wherein said ring is substituted with at 1-4groups independently selected from -D-E, oxo, NO₂, halogen, CN, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; D is a covalent bond or abivalent C₁-C₆ saturated or unsaturated, straight or branched,hydrocarbon chain, wherein one or two methylene units of D areoptionally and independently replaced by —NR⁸—, —S—, —O—, —C(O)—, —SO—,or —SO₂—; E is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein said alkyl, alkenyl or alkynyl is optionally substituted withoxo, halogen, or CN; and each R⁸ is independently hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₁-C₆ alkoxy, —S(O)₂—C₂-C₄ alkenyl, or anoptionally substituted group selected from phenyl, a 4-7 memberedheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; R² is selected from phenyl, a 3-7 memberedcycloalkyl, C₂-C₄ alkyl, or CF₃, wherein the phenyl or cycloalkyl isoptionally substituted with a substituent selected from methyl orfluoro; each R³ is independently selected from halo, —(C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —C₁-C₄ fluoroalkyl, —C(O)—O—(C₁-C₄ alkyl),-phenyl, -heteroaryl, C₃-C₇ cycloalkyl, —CH₂—N(C₁-C₄ alkyl)₂,C(O)—N—(C₁-C₄ alkyl)₂, —C(O)—NH—(C₁-C₄ alkyl), —C₁-C₄ alkyl optionallysubstituted with one or more halo or —OH, or two R³s are taken togetherto form a 3-8 saturated ring or a fused phenyl wherein said saturatedring or fused phenyl is optionally substituted with 1 to 2 methyl; R⁴ isselected from hydrogen, —CN, halo, C₁-C₄ alkoxy, —CH₂NH(C₁-C₄ alkyl),C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), C₁-C₄fluoroalkyl, C(O)—N—(C₁-C₄ alkyl)₂, —C(O)—NH—(C₁-C₄ alkyl),—C(O)—O—(C₁-C₄ alkyl), —C(O)—OH, —S(O)₂—(C₁-C₄ alkyl), and a 5-memberedheteroaryl; R⁵ is selected from: —C(O)—(C₁-C₅ alkyl), —C(O)—(C₂-C₆alkenyl), —C(O)—(C₀-C₂ alkylene)-Q, —C(O)—(C₁-C₄ alkenylene)-Q,—C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₀-C₂ alkylene)-Q, —C(O)—O—(C₀-C₂alkylene)-Q, —C(O)—(C₁-C₂ alkylene)-O—(C₀-C₂ alkylene)-Q, —C(O)—C(O)-Q,—S(O)₂-Q, —C(O)—(C₁-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl), —C(O)—N(R⁶)—(C₁-C₄alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—N(R⁶)—(C₁-C₄alkylene)-C(O)—O—(C₁-C₄ alkyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₁-C₆alkyl), —C(O)—(C₀-C₂ alkylene)N(R⁶)—(C₂-C₆ alkynyl), —C(O)—(C₀-C₂alkylene)-N(R⁶)—(C₂-C₆ alkenyl), —C(O)—(C₀-C₂ alkylene)-N(R⁶)—(C₀-C₂alkylene)-O—(C₁-C₄ alkyl), —C(O)—(C₁-C₂ alkylene)-O—(C₁-C₄ alkyl),—C(O)—(C₁-C₂ alkylene)-C(O)C(O)N(R)(C₁-C₄ alkyl), —C(O)—O—(C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —(C₀-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl),—(C₀-C₄ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₄ alkylene)-O—(C₁-C₄alkyl), —C(O)—(C₁-C₂ alkylene)-S(O)₀₋₂-(C₁-C₄ alkyl), —S(O)₂—(C₁-C₄alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)C(O)N(R⁶)(C₁-C₆ alkyl), —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂—(C₁-C₆ alkyl), or —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂Q, wherein: any alkylene moiety present in R⁵ isoptionally substituted with OCH₃, OH or F; any terminal methyl moietypresent in R⁵ is optionally replaced with —CH₂OH, CF₃, CH₂F, —CH₂Cl,C(O)CH₃, C(O)CF₃, CN, —OCH₃, —C(O)H, —OP(O)(OH)₂, —OP(O)(C₁-C₄ alkoxy)₂or CO₂H; each R⁶ is independently selected from hydrogen and methyl; Qis selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, whereinQ is optionally substituted with up to 3 substituents independentlyselected from C₁-C₄ alkyl optionally substituted with OH, C₁-C₄ alkoxy,—C(O)O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-(C₁-C₄ alkoxy), —CN, —OH,fluoro, chloro, and bromo; R⁹ is selected from aryl and heteroaryl,wherein each aryl or heteroaryl is optionally substituted with one ormore substituents selected from -G-L-M, halo, C₁-C₆ alkyl, —C≡N, ═O,—CF₃ and —OCF₃; and m is 0, 1, 2 or
 3. 2. The compound of claim 1,wherein: Y is —N(R⁵)— or —CH(R⁵)—; each R^(1a) and R^(1b) isindependently hydrogen, —C₁-C₄ alkyl, —N(R⁷)(C₁-C₄ alkylene)-N(R⁷)(C₁-C₄alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R⁷)-aryl,—N(R⁷)C(O)-aryl, —(C₁-C₄ alkylene)-aryl, —(C₁-C₄ alkylene)-heteroaryl,—O—(C₁-C₄ alkylene)-aryl, —O—(C₁-C₄ alkylene)-heteroaryl, —O—(C₁-C₄alkylene)-heterocyclyl, —N(R⁷)-aryl, or —N(R⁷)-heteroaryl, wherein: atleast one of R^(1a) and R^(1b) is not hydrogen or methyl; any alkylenemoiety present in R^(1a) or R^(1b) is optionally substituted with OH orF; each R⁷ is independently selected from hydrogen and C₁-C₄ alkyl; andany aryl, heteroaryl, or hetercylyl of R^(1a) or R^(1b) is optionallysubstituted with one or more substituents selected from -G-L-M, halo,C₁-C₆ alkyl, —C≡N, ═O, —CF₃ and —OCF₃; G is a bond or a bivalent C₁-C₆saturated or unsaturated, straight or branched hydrocarbon chain whereinoptionally one, two or three methylene units of the hydrocarbon chainare independently replaced by —NR⁸—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,—SO—, —SO₂—, —C(═S)—, —C(═NR⁸)—, —N═N—, or —C(═N₂)—; L is a covalentbond or a bivalent C₁₋₈ saturated or unsaturated, straight or branched,hydrocarbon chain, wherein one, two, or three methylene units of L areoptionally and independently replaced by cyclopropylene, —N(R⁸)C(O)—,—C(O)N(R⁸)—, —N(R⁸)SO₂—, SO₂N(R⁸)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,—SO—, —SO₂—, —C(═S)—, —C(═NR⁸)—, —N═N—, or —C(═N₂)—; M is E, or a 3-10membered monocyclic or bicyclic, saturated, partially unsaturated, oraromatic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein said ring is substituted withat 1-4 groups independently selected from -D-E, oxo, NO₂, halogen, CN,C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; D is a covalent bond or abivalent C₁-C₆ saturated or unsaturated, straight or branched,hydrocarbon chain, wherein one or two methylene units of D areoptionally and independently replaced by —NR⁸—, —S—, —O—, —C(O)—, —SO—,or —SO₂—; E is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein said alkyl, alkenyl or alkynyl is optionally substituted withoxo, halogen, or CN; and each R⁸ is independently hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, or an optionally substituted groupselected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; R² is selected from phenyl, a3-7 membered cycloalkyl, and C₂-C₄ alkyl, wherein the phenyl orcycloalkyl is optionally substituted with a substituent selected frommethyl or fluoro; each R³ is independently selected from —C₁-C₄ alkyl,—(C₁-C₄ alkyl)-O—(C₁-C₄ fluoroalkyl, —C(O)—O—(C₁-C₄ alkyl), -phenyl,-heteroaryl, C₃-C₇ cycloalkyl, —CH₂—N(C₁-C₄ alkyl)₂, C(O)—N—(C₁-C₄alkyl)₂, and —C(O)—NH—(C₁-C₄ alkyl), or or two R³s are taken together toform a 3-8 saturated ring or a fused phenyl wherein said saturated ringor fused phenyl is optionally substituted with 1 to 2 methyl groups; R⁴is selected from hydrogen, —CN, halo, C₁-C₄ alkoxy, —CH₂NH(C₁-C₄ alkyl),C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), C₁-C₄fluoroalkyl, C(O)—N—(C₁-C₄ alkyl)₂, —C(O)—NH—(C₁-C₄ alkyl),—C(O)—O—(C₁-C₄ alkyl), —C(O)—OH, —S(O)₂—(C₁-C₄ alkyl), and a 5-memberedheteroaryl; R⁵ is selected from: —C(O)—(C₁-C₄alkyl), —C(O)—(CH₂)₀₋₂-Q,—C(O)—(CH₂)₀₋₂—N(R⁶)—(CH₂)₀₋₂-Q, —C(O)—O—(CH₂)₁₋₂-Q,—C(O)—(CH₂)₁₋₂—O—(CH₂)₀₋₂-Q, —C(O)—C(O)-Q, —S(O)₂-Q, —C(O)—(C₁-C₄alkylene)-O—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)—O—(C₁-C₄alkyl), —C(O)—N(R⁶)—(C₁-C₄ alkylene)-O—C(O)—(C₁-C₄ alkyl),—C(O)—N(R⁶)—(C₁-C₄ alkylene)-C(O)—O—(C₁-C₄ alkyl),—C(O)—(CH₂)₀₋₂—N(R⁶)—(C₁-C₆ alkyl), —C(O)—(CH₂)₀₋₂—N(R⁶)—(C₂-C₆alkynyl), —C(O)—(CH₂)₀₋₂—N(R⁶)—(C₂-C₆ alkenyl),—C(O)—(CH₂)₀₋₂—N(R⁶)—(CH₂)₀₋₂—O—(C₁-C₄ alkyl), —C(O)—(CH₂)₁₋₂—O—(C₁-C₄alkyl), —C(O)—O—(C₁-C₄ alkylene)-O—(C₁-C₄ alkyl),—(CH₂)₀₋₄—O—C(O)—(C₁-C₄ alkyl), —(CH₂)₀₋₄—C(O)—O—(C₁-C₄ alkyl),—(CH₂)₀₋₄—O—(C₁-C₄ alkyl), —C(O)—(CH₂)₁₋₂—S—(C₁-C₄ alkyl), —S(O)₂—(C₁-C₄alkyl), —C(O)—(C₁-C₄ alkylene)-C(O)C(O)N(R⁶)(C₁-C₆ alkyl), —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂—(C₁-C₆ alkyl), and —C(O)—(C₁-C₄alkylene)-N(R⁶)S(O)₂Q, wherein: any alkylene moiety present in R⁵ isoptionally substituted with OH or F; any terminal methyl moiety presentin R⁵ is optionally replaced with —CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃,or C(O)CF₃; each R⁶ is independently selected from hydrogen and methyl;Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl,wherein Q is optionally substituted with up to 3 substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, —CN, fluoro,chloro, and bromo; and m is 0, 1, 2 or
 3. 3. The compound of claim 1,wherein R⁴ is selected from —CN or C(O)—O—C₁-C₄ alkyl.
 4. The compoundof claim 1, wherein R⁴ is


5. The compound of claim 1, wherein Y is —N(R⁵)—.
 6. The compound ofclaim 6, wherein R⁵ is —C(O)—(C₁-C₃ alkyl)-O—(C₁-C₂ alkyl), —C(O)-Q,—C(O)—(C₁-C₅ alkyl), —C(O)—(C₁-C₂ alkylene)-Q, —C(O)—(C₂-C₄ alkenyl),—C(O)O—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkenylene)-Q; wherein: anyalkylene moiety present in R⁵ is optionally substituted with OH; anyterminal methyl moiety present in R⁵ is optionally replaced with —OH,CF₃, OCH₃, —C(O)H, OP(O)(C₁-C₄ alkoxy)₂, or —OP(O)(OH)₂ (or a salt of—OP(O)(OH)₂).
 7. The compound of claim 6, wherein Q is cyclopropyl,cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl,tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each memberof Q is optionally substituted with one substituent independentlyselected from C₁-C₄ alkyl optionally substituted with OH, C₁-C₄ alkoxy,alkylene)-(C₁-C₄ alkoxy), and —OH.
 8. The compound of claim 1, whereinR^(1a) is H and R^(1b) is aryl, heteroaryl, heterocyclyl,alkylene)-aryl, alkylene)-heteroaryl, —O—(C₀-C₄ alkylene)-aryl,—O—(C₀-C₄ alkylene)-heteroaryl, —N(R⁷)-aryl, —N(R⁷)heteroaryl,—N(R⁹)-aryl, or —N(R⁹)-heteroaryl; wherein said aryl or heteroaryl issubstituted with -G-L-M, CH₃, or CN.
 9. The compound of claim 8, whereinaryl associated with R^(1b) is phenyl.
 10. The compound of claim 8,wherein heteroaryl is associated with R^(1b) pyridyl, pyrimidinyl,naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl,imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl,pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl,quinazolinyl, pyridazinyl or pyrazolyl.
 11. The compound of claim 8,wherein heterocyclyl is associated with R^(1b) benzodioxole,pyridazinone, benzoxazolone, indolinone, N-methylindolinone,piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl,dihydropyrrolyl and said phenyl, pyridyl, pyrimidinyl, naphthyridinyl,quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl,benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl,indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl,pyridazinyl, pyrazolyl, benzodioxole, pyridazinone, benzoxazolone,indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone,tetrahydropyridinyl, or dihydropyrrolyl
 12. The compound of claim 9,wherein aryl, heteroaryl or heterocyclyl associated with R^(1b) issubstituted with -G-L-M, —CF₃, —OCF₃, halo (e.g., fluoro, chloro orbromo), CH₃, or CN.
 13. The compound of claim 1, wherein R^(1a) ismethyl and R^(1b) is aryl, heteroaryl, heterocyclyl, —O—(C₀-C₄alkylene)-aryl, or —O—(C₀-C₄ alkylene)-heteroaryl.
 14. The compound ofclaim 13, wherein R^(1a) is methyl and R^(1b) is aryl, heteroaryl,heterocyclyl, —O—(CH₂)-aryl, —O—CH(CH₃)-aryl, —O—(CH₂)-heteroaryl or—O—CH(CH₃)-heteroaryl.
 15. The compound of claim 13, wherein arylassociated with R^(1b) is phenyl or naphthyl.
 16. The compound of claim13, wherein heteroaryl associated with R^(1b) is quinolinyl, pyrazolyl,isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl.
 17. Thecompound of claim 13, wherein heterocyclyl associated with R^(1b) istetrahydropyridinyl and said phenyl, pyridyl, pyrimidinyl, indolyl, orpyrazolyl.
 18. The compound of claim 13, wherein aryl, heteroaryl orheterocyclyl associated with R^(1b) is substituted with -G-L-M, halo,CH₃, or CN.
 19. The compound of claim 8, wherein -G-L-M:

C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, tetrazolyl, morpholino,piperazinyl, pyrrolidinone, pyrazolyl, benzyl, —(CH₂)₁₋₄—SH,—(CH₂)₁₋₄—NH₂, —NH₂, —(CH₂)₁₋₄—OH, —N(H)C(O)OCH(CH₃)₃, —(CH₂)₁₋₄—OCH₃,—NH—(CH₂)₁₋₄—OH, —C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkenyl),—O—(CH₂)₁₋₄—C(O)—O—(C₁-C₄ alkyl), —C(O)NH₂, —(CH₂)₁₋₄C(O)CH₃,—N(CH₃)(CH₃), —NHC(O)(C₂-C₄ alkenyl), —NHC(O)(C₂-C₄ alkyl),—SO₂(CH₂)₁₋₄, —(CH₂)₁₋₄—NHSO₂Me, —NHSO₂(CH₂)₁₋₄, —O—SO₂CF₃,—SO₂NH—(C₁-C₄ alkyl), —SO₂NH—(C₂-C₄ alkenyl), SO₂—NH₂ or —NHSO₂Me
 20. Apharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable carrier.
 21. The composition of claim 20,further comprising a second therapeutic agent.
 22. A method of treatinga cancer characterized by the presence of an IDH1 mutation, wherein theIDH1 mutation result in a new ability of the enzyme to catalyze theNAPH-dependent reduction of a-ketoglutarate to R(−)-2-hydroxyglutaratein a patient, comprising the step of administering to the patient inneed thereof a composition of claim
 20. 23. The method of claim 22,wherein the IDH1 mutation is an IDH1 R132H or IDH1 R132C mutation. 24.The method of claim 23, wherein the cancer is selected from glioma(glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-smallcell lung cancer and cholangiocarcinomas, cholangiocarcinomas,chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferativeneoplasm (MPN), or colon cancer.
 25. The method of claim 22, furthercomprising administering to the patient in need thereof a secondtherapeutic agent.